Piperidine/piperazine derivatives

ABSTRACT

The invention relates to a DGAT inhibitor of formula (I): including any stereochemically isomeric form thereof, wherein A represents CH or N; the dotted line represents an optional bond in case A represents a carbon atom; X represents —C(═O)—; —O—C(═O)—; C(═O)—C(═O)—; —NR x —C(═O)—; —Z 1 —C(O)—; —Z 1 —NR x —C(═O)—; —C(═O)—Z 1 —; —NR x —C(═O)—Z 1 —; —S(═O)p-; —C(═S)—; —NR x —C(═S)—; —Z 1 —C(═S)—; —Z 1 —NR x —C(═S)—; —C(═S)—Z1-; NR x —C(═S)—Z—; Y represents NR x —C(= 0 )-Z 2 —; —NR x —C(= 0 )-Z 2 —NR y —; —NR x —C(= 0 )-Z  2 —NR y —C(= 0 )—; —NR x —C(= 0 )-Z 2 —NR y —C(= 0 )-; O—; —NR x —C(= 0 )-Z 2 - 0 -; —NR x —C(= 0 )-Z 2 - 0 -C(= 0 )-; —NR x —C(= 0 )-Z 2 —C(= 0 )-; —NR x —C(= 0 )-Z 2 —C(= 0 )-; —NR x —C(= 0 )- 0 -Z 2 —C(= 0 )-; —NR x —C(= 0 )- 0 -Z 2 —C(= 0 )- 0 -; —NR x —C(═O)—O—Z 2 —O—C(═O)—; —NR x —C(═O)—Z 2 —C(═O)—NR y —; —NR x —C(═O)—Z 2 —NR y —C(= 0 )-NR y —; —C(═O)—Z 2 —; —C(═O)—Z 2 —O—; —C(= 0 )-NR x —Z 2 —; —C(= 0 )-NR x —Z 2 - 0 -; —C(= 0 )-NR x —Z 2 —C(= 0 )- 0 -; —C(= 0 )-NR x —Z 2 - 0 -C(= 0 )-; —C(= 0 )-NR x —Z 2 —NR y —; —C(= 0 )—NR x —Z 2 —NR y —C(= 0 )-; —C(= 0 )-NR x —Z 2 —NR y —C(= 0 )- 0 -; R 1  represents C 1-12 alkyl optionally substituted with cyano, C 1-4 alkyloxy, C 1-4 alkyl-oxyC 1-4 alkyloxy, C 3-6 Cycloalkyl or aryl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl; adamantanyl; aryl 1 ; aryl 1 C 1-6 alkyl; Het 1 ; or Het 1 C 1-6 alkyl; provided that when Y represents —NR x —C(═O)—Z 2 —; —NR x —C(= 0 )-Z 2 —NR y ; —NR x —C(═O)—Z 2 —C(═O)—NR y —; —C(═O)—Z 2 —; —NR x —C(= 0 )-Z 2 —NR y —C(= 0 )—NR y —; —C(═O)—NR—Z 2 —; —C(═O)—NR—O—Z 2 —; or —C(= 0 )-NR x —Z 2 —NR y —; then R 1  may also represent hydrogen; R 2  represents hydrogen, C 1-12 alkyl, C 2-6 alkenyl or R 3 ; provided that if X represents —O—C(═O)—; the R 2  O represents R 3 ; and provided that (A) is excluded; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds.

FIELD OF THE INVENTION

The present invention relates to the use of a DGAT inhibitor, inparticular a DGAT1 inhibitor, for the manufacture of a medicament forthe prevention or the treatment of a disease by elevating the levels ofone or more satiety hormones, in particular GLP-1. The present inventionalso concerns piperidine/piperazine derivatives having DGAT inhibitoryactivity, in particular DGAT1 inhibitory activity. The invention furtherrelates to methods for their preparation and pharmaceutical compositionscomprising them. The invention also relates to the use of said compoundsfor the manufacture of a medicament for the prevention or the treatmentof a disease mediated by DGAT, in particular DGAT 1.

BACKGROUND TO THE INVENTION

Triglycerides represent the major form of energy stored in eukaryotes.Disorders or imbalances in triglyceride metabolism are implicated in thepathogenesis of and increased risk for obesity, insulin resistancesyndrome and type II diabetes, nonalcoholic fatty liver disease andcoronary heart disease (see, Lewis, et al, Endocrine Reviews (2002)23:201 and Malloy and Kane, Adv. Intern. Med. (2001) 47:11 1).Additionally, hypertriglyceridemia is often an adverse consequence ofcancer therapy (see, Bast, et al. Cancer Medicine, 5th Ed., (2000) B. C.Decker, Hamilton, Ontario, CA).

A key enzyme in the synthesis of triglycerides is acylCoA:diacylglycerol acyltransferase, or DGAT. DGAT is a microsomal enzymethat is widely expressed in mammalian tissues and that catalyzes thejoining of 1,2-diacylglycerol (DAG) and fatty acyl CoA to formtriglycerides (TG) at the endoplasmic reticulum (reviewed in Chen andFarese, Trends Cardiovasc. Med. (2000) 10: 188 and Farese, et al, Curr.Opin. Lipidol. (2000) 11:229). It was originally thought that DGATuniquely controlled the catalysis of the final step of acylation ofdiacylglycerol to triglyceride in the two major pathways fortriglyceride synthesis, the glycerol phosphate and monoacylglycerolpathways. Because triglycerides are considered essential for survival,and their synthesis was thought to occur through a single mechanism,inhibition of triglyceride synthesis through inhibiting the activity ofDGAT has been largely unexplored.

Genes encoding mouse DGAT1 and the related human homologs ARGP1 (humanDGAT1) and ARGP2 (human ACAT2) now have been cloned and characterized(Cases, et al, Pro.c Nat.l Acad. Sci. (1998) 95:13018; Oelkers, et al,J. Biol. Chem. (1998) 273:26765). The gene for mouse DGAT1 has been usedto create DGAT knock-out mice to better elucidate the function of theDGAT gene.

Unexpectedly, mice unable to express a functional DGAT1 enzyme (Dgat1−/−mice) are viable and still able to synthesize triglycerides, indicatingthat multiple catalytic mechanisms contribute to triglyceride synthesis(Smith, et al, Nature Genetics (2000) 25:87). Other enzymes thatcatalyze triglyceride synthesis, for example, DGAT2 and diacylglyceroltransacylase, also have been identified (Cases, et al, J. Biol. Chem.(2001) 276:38870). Gene knockout studies in mice have revealed thatDGAT2 plays a fundamental role in mammalian triglyceride synthesis andis required for survival. DGAT2 deficient mice are lipopenic and diesoon after birth, apparently from profound reductions in substrates forenergy metabolism and from impaired permeability barrier function in theskin. (Farese, et al., J. Biol. Chem. (2004) 279: 11767).

Significantly, Dgat1−/− mice are resistant to diet-induced obesity andremain lean. Even when fed a high fat diet (21% fat) Dgat1−/− micemaintain weights comparable to mice fed a regular diet (4% fat) and havelower total body triglyceride levels. The obesity resistance in Dgat1−/−mice is not due to decreased caloric intake, but the result of increasedenergy expenditure and decreased resistance to insulin and leptin(Smith, et al, Nature Genetics (2000) 25:87; Chen and Farese, TrendsCardiovasc. Med. (2000) 10: 188; and Chen, et al, J. Clin. Invest.(2002) 109:1049). Additionally, Dgat1−/− mice have reduced rates oftriglyceride absorption (Buhman, et al, J. Biol. Chem. (2002)277:25474). In addition to improved triglyceride metabolism, Dgat1−/−mice also have improved glucose metabolism, with lower glucose andinsulin levels following a glucose load, in comparison to wild-type mice(Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188).

The finding that multiple enzymes contribute to catalyzing the synthesisof triglyceride from diacylglycerol is significant, because it presentsthe opportunity to modulate one catalytic mechanism of this biochemicalreaction to achieve therapeutic results in an individual with minimaladverse side effects. Compounds that inhibit the conversion ofdiacylglycerol to triglyceride, for instance by specifically inhibitingthe activity of DGAT1, will find use in lowering corporealconcentrations and absorption of triglycerides to therapeuticallycounteract the pathogenic effects caused by abnormal metabolism oftriglycerides in obesity, insulin resistance syndrome and overt type IIdiabetes, congestive heart failure and atherosclerosis, and as aconsequence of cancer therapy.

Because of the ever increasing prevalence of obesity, type II diabetes,heart disease and cancer in societies throughout the world, there is apressing need in developing new therapies to effectively treat andprevent these diseases. Therefore there is an interest in developingcompounds that can potently and specifically inhibit the catalyticactivity of DGAT, in particular DGAT1.

We have now unexpectedly found that the compounds of the presentinvention exhibit DGAT inhibitory activity, in particular DGAT1inhibitory activity, and can therefore be used to prevent or treat adisease associated with or mediated by DGAT, such as for exampleobesity, type II diabetes, heart disease and cancer. The compounds ofthe invention differ from the prior art compounds in structure, in theirpharmacological activity, pharmacological potency, and/orpharmacological profile.

We have also unexpectedly found that DGAT inhibitors can be used toelevate the levels of one or more satiety hormones, in particularglucagon-like-peptide-1 (GLP-1) and therefore DGAT inhibitors, inparticular DGAT1 inhibitors, can also be used to prevent or treat adisease which can benefit from elevated levels of a satiety hormone, inparticular GLP-1. Glucagon-like peptide 1 (GLP-1) is an intestinalhormone which generally stimulates insulin secretion duringhyperglycemia, suppresses glucagon secretion, stimulates (pro) insulinbiosynthesis and decelerates gastric emptying and acid secretion. GLP-1is secreted from L cells in the small and large bowel following theingestion of fat and proteins. GLP-1 has been suggested, among otherindications, as a possible therapeutic agent for the management of type2 non-insulin-dependent diabetes mellitus as well as related metabolicdisorders, such as obesity.

Thus, by the present finding, a disease which can benefit from elevatedlevels of GLP-1 can be treated with small molecules (compared to largemolecules such as proteins or protein-like compounds, e.g. GLP-1analogues).

Background Prior Art

WO 2006/034441 discloses heterocyclic derivatives and their use asstearoyl CoA desaturase inhibitors (SCD-1 inhibitors).

WO 2006/086445 relates to a combination therapy of a SCD-1 inhibitor andanother drug to treat adverse weight gain.

WO 2006/004200 and JP2007131584 relate to urea and amino derivativeshaving DGAT inhibitory activity. WO 2004/047755 relates to fusedbicyclic nitrogen—Containing heterocycles having DGAT inhibitoryactivity. W02005/072740 relates to an anorectic action of a compoundhaving DGAT inhibitory activity.

DESCRIPTION OF THE FIGURES

FIG. 1 describes the postprandial GLP-1 plasma profile for compound 223(dose of 0.3 mg/kg), determined according to the protocol described inpharmacological example D.B) hereinafter.

DESCRIPTION OF THE INVENTION

The present invention relates to the use of a DGAT inhibitor for themanufacture of a medicament for the prevention or the treatment, inparticular for the treatment, of a disease which can benefit fromelevated levels of one or more satiety hormones, in particular GLP-1.

The present invention further relates to a compound of formula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—;    —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—;    —S(═O)p-; —C(═S)—; —NR^(x)—C(═S)—; —Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—;    —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—;-   Z¹ represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl or amino; and wherein two hydrogen atoms    attached to the same carbon atom in C₁₋₆alkanediyl may optionally be    replaced by C₁₋₆alkanediyl;-   Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—;-   NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—; —NR^(x)—C(═O)—Z²—O—;    —NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—C(═O)—;    —NR^(x)—C(═O)—O—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—O—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; —C(═O)—Z²—O—;    —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;    —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;    —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;    —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—;-   Z² represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z² may optionally be replaced by    C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹;    aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; provided that when Y    represents —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also    represent hydrogen;-   R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl or R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzo    furanyl or a 6-membered aromatic heterocycle containing 1 or 2 N    atoms, wherein said C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or heterocycle may    optionally be substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently selected from hydroxyl; carboxyl; halo;    C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;    C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;    aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het;    Het-C₁₋₄alkyl; aryl; R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms each    independently selected from O, S, S(═O)_(p) or N; and which    heterocycle may optionally be substituted with C₁₋₄alkyl;-   R⁸ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with    hydroxyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; amino carbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₆alkyl)amino;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi-or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with C₁₋₄alkyloxy, amino or mono-or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally    substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi- or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;    aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;    arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;    C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—;    aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—;    Het; HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   p represents 1 or 2;-   provided that if X represents —O—C(═O)—, then R² represents R³; and

provided that is excluded; a N-oxide thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof.

The present invention also relates to the use of a compound of formula(I) for the manufacture of a medicament for the prevention or thetreatment of a disease which can benefit from elevated levels of one ormore satiety hormones, in particular GLP-1, in particular the presentinvention relates to the use of a compound of formula (I) for themanufacture of a medicament for the treatment of a disease which canbenefit from elevated levels of GLP-1.

The present invention further relates to the use of a compound offormula (I) for the manufacture of a medicament for the prevention orthe treatment of a disease mediated by DGAT, in particular the presentinvention relates to the use of a compound of formula (I) for themanufacture of a medicament for the prevention or the treatment of adisease which can benefit from inhibition of DGAT, in particular for thetreatment of a disease which can benefit from inhibition of DGAT, inparticular DGAT1, wherein the compound of formula (I) is a compound offormula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—;    —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—;    —S(═O)p-; —C(═S)—; —NR^(x)—C(═S)—; —Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—;    —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—;-   Z¹ represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl or amino; and wherein two hydrogen atoms    attached to the same carbon atom in C₁₋₆alkanediyl may optionally be    replaced by C₁₋₆alkanediyl;-   Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—C(═O)—; —NR^(x)—C(═O)—O—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; —C(═O)—Z²—O—;    —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;    —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;    —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;    —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—;-   Z² represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z² may optionally be replaced by    C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹;    aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; provided that when Y    represents —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also    represent hydrogen;-   R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl or R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzo    furanyl or a 6-membered aromatic heterocycle containing 1 or 2 N    atoms, wherein said C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered    aromatic heterocycle containing 1 or 2 N atoms may optionally be    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    selected from hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally    substituted with hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally    substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted    with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl;    R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het;    Het-C₁₋₄alkyl; aryl; R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms each    independently selected from O, S, S(═O)_(p) or N; and which    heterocycle may optionally be substituted with C₁₋₄alkyl;-   R⁸ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with    hydroxyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; amino carbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₆alkyl)amino;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi-or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with C₁₋₄alkyloxy, amino or mono-or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally    substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi- or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;    aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;    arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;    C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—;    aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—;    Het; HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   p represents 1 or 2;-   provided that if X represents —O—C(═O)—, then R² represents R³;-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof

As used hereinbefore or hereinafter C₀₋₃alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 0 (then it represents a direct bond) to 3 carbon atoms suchas methyl, ethyl, propyl, 1-methyl-ethyl; C₁₋₂alkyl as a group or partof a group defines straight or branched chain saturated hydrocarbonradicals having 1 or 2 carbon atoms such as methyl, ethyl; C₁₋₄alkyl asa group or part of a group defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as methyl,ethyl, propyl, 1-methylethyl, butyl; C₁₋₅alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 5 carbon atoms such as the group defined for C₁₋₄alkyland pentyl, 2-methylbutyl and the like; C₁₋₆alkyl as a group or part ofa group defines straight or branched chain saturated hydrocarbonradicals having from 1 to 6 carbon atoms such as the group defined forC₁₋₄alkyl and for C₁₋₅alkyl and hexyl, 2-methylpentyl and the like;C₁₋₁₂alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 12 carbon atomssuch as the group defined for C₁₋₆alkyl and heptyl, 2-methylheptyl andthe like; C₁₋₆alkanediyl defines straight or branched chain saturatedbivalent hydro-carbon radicals having from 1 to 6 carbon atoms such asmethylene, 1,2-ethanediyl or 1,2-ethylidene, 1,3-propanediyl or1,3-propylidene, 1,4-butanediyl or 1,4-butylidene, 1,5-pentanediyl andthe like; C₂₋₄alkenyl as a group or part of a group defines straight orbranched chain hydrocarbon radicals having from 2 to 4 carbon atoms andhaving a double bond such as ethenyl, propenyl, butenyl and the like;C₂₋₆alkenyl as a group or part of a group defines straight or branchedchain hydrocarbon radicals having from 2 to 6 carbon atoms and having adouble bond such as the group defined for C₂₋₄alkenyl and pentenyl,hexenyl, 3-methylbutenyl and the like; C₂₋₆alkenediyl defines straightor branched chain bivalent hydrocarbon radicals having from 2 to 6carbon atoms and having a double bond such as 1,2-ethenediyl,1,3-propenediyl, 1,4-butenediyl, 1,5-pentenediyl and the like;

-   C₂₋₆alkynediyl as a group or part of a group defines straight or    branched chain bivalent hydrocarbon radicals having from 2 to 6    carbon atoms and having a triple bond such as 1,2-ethynediyl,    1,3-propynediyl, 1,4-butynediyl, 1,5-pentynediyl and the like;    C₃₋₆cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl    and cyclohexyl.

The term halo is generic to fluoro, chloro, bromo and iodo. As usedhereinbefore or hereinafter, polyhaloC₁₋₆alkyl as a group or part of agroup is defined as C₁₋₆alkyl substituted with one or more, such as forexample 2, 3, 4 or 5 halo atoms, for example methyl substituted with oneor more fluoro atoms, for example, difluoromethyl or trifluoromethyl,1,1-difluoro-ethyl, 1,1-difluoro-2,2,2-trifluoro-ethyl and the like. Incase more than one halogen atoms are attached to a C₁₋₆alkyl groupwithin the definition of polyhaloC₁₋₆alkyl, they may be the same ordifferent.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom. Oxo means ═O.

The radical Het or Het¹ as defined hereinabove may be an optionallysubstituted monocyclic non-aromatic or aromatic heterocycle containingat least one heteroatom, in particular 1, 2 or 3 heteroatoms, eachindependently selected from O, S, S(═O)_(p) or N; or an optionallysubstituted bi- or tricyclic non-aromatic or aromatic heterocyclecontaining at least one heteroatom, in particular 1, 2, 3, 4 or 5heteroatoms, each independently selected from O, S, S(═O)_(p) or N.Examples of such unsubstituted monocyclic heterocycles comprise, but arenot limited to, non-aromatic (fully saturated or partially saturated) oraromatic 4-, 5-, 6- or 7-membered monocyclic heterocycles such as forexample azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl,isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl,hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, trithianyl, hexahydrodiazepinyl, pyrrolinyl, imidazolinyl,pyrazolinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, pyranyl and the like. Examples of such unsubstituted bicyclicor tricyclic heterocycles comprise, but are not limited to, non-aromatic(fully saturated or partially saturated) or aromatic 8- to 17-memberedbicyclic or tricyclic heterocycles such as for exampledecahydroquinolinyl, octahydroindolyl, 2,3-dihydrobenzo furanyl,1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolinyl, benzofuryl,isobenzofuryl, benzothienyl, isobenzothienyl, indolizinyl, indolyl,isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl,pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl,pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl,furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl,imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl,furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl,isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl,imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl,triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl,triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,imidazoimidazolyl, imidazopyrazolyl; isoxazolotriazinyl,isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl,thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl,thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl and the like. Optionalsubstituents for Het heterocycles are hydroxyl; oxo; carboxyl; halo;C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino or mono-ordi(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl. Optional substituents for Het'substituents are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—;hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl;nitro; amino; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—.

Examples of a 6-membered aromatic heterocycle containing 1 or 2 N atomsin the definition of R³ are pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl.

When any variable occurs more than one time in any constituent (e.g.aryl, Het), each definition is independent.

The term Het or Het¹ is meant to include all the possible isomeric formsof the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and2H-pyrrolyl.

The carbocycles or heterocycles covered by for instance the terms aryl,aryl¹, Het, Het¹ or R³ may be attached to the remainder of the moleculeof formula (I) through any ring carbon or heteroatom as appropriate, ifnot otherwise specified. Thus, for example, when the heterocycle isimidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and thelike, or when the carbocycle is naphthalenyl, it may be 1-Naphthalenyl,2-naphthalenyl and the like.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

When X is defined as for instance —NR^(x)—C(═O)—, this means that thenitrogen of NR^(x) is linked to the R² substituent and the carbon atomof C(═O) is linked to the nitrogen of the ring

Thus the left part of the bivalent radical in the definition of X islinked to the R² substituent and the right part of the bivalent radicalin the definition of X is linked to the ring moiety

When Y is defined as for instance —NR^(x)—C(═O)—Z²—, this means that thenitrogen of NR^(x) is linked to the phenyl ring and the Z² is linked tothe R¹ substituent. Thus the left part of the bivalent radical in thedefinition of Y is linked to the phenyl ring and the right part of thebivalent radical in the definition of Y is linked to R¹ substituent.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinbefore or hereinafter that substituents can beselected each independently out of a list of numerous definitions, suchas for example for R⁴ and R⁵, all possible combinations are intendedwhich are chemically possible.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable salts as mentioned hereinbefore orhereinafter are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The latter can conveniently be obtained by treating the base formwith such appropriate acids as inorganic acids, for example, hydrohalicacids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid;nitric acid; phosphoric acid and the like; or organic acids, forexample, acetic, propanoic, hydroxy-acetic, 2-hydroxypropanoic,2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and thelike acids. Conversely the salt form can be converted by treatment withalkali into the free base form.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases. Thepharmaceutically acceptable salts as mentioned hereinbefore orhereinafter are meant to also comprise the therapeutically activenon-toxic metal or amine addition salt forms (base addition salt forms)which the compounds of formula (I) are able to form. Appropriate baseaddition salt forms comprise, for example, the ammonium salts, thealkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like.

Conversely the salt form can be converted by treatment with acid intothe free acid form.

The term salt also comprises the quaternary ammonium salts (quaternaryamines) which the compounds of formula (I) are able to form by reactionbetween a basic nitrogen of a compound of formula (I) and an appropriatequaternizing agent, such as, for example, an optionally substitutedC₁₋₆alkylhalide, arylhalide, C₁₋₆alkyl-carbonylhalide,arylcarbonylhalide, or arylC₁₋₆alkylhalide, e.g. methyliodide orbenzyliodide. Other reactants with good leaving groups may also be used,such as for example C₁₋₆alkyl trifluoromethanesulfonates, C₁₋₆alkylmethanesulfonates, and C₁₋₆alkyl p-toluenesulfonates. A quaternary aminehas a positively charged nitrogen. Pharmaceutically acceptablecounterions include chloro, bromo, iodo, trifluoroacetate, acetate,triflate, sulfate, sulfonate. The counterion of choice can be introducedusing ion exchange resins.

The term solvate comprises the hydrates and solvent addition forms whichthe compounds of formula (I) are able to form, as well as the saltsthereof. Examples of such forms are e.g. hydrates, alcoholates and thelike.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several tertiary nitrogen atomsare oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of formula (I) andtheir N-oxides, salts, and solvates may contain one or more centers ofchirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore orhereinafter defines all the possible stereoisomeric forms which thecompounds of formula (I), and their

N-oxides, salts, or solvates may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically isomeric forms, said mixtures containingall diastereomers and enantiomers of the basic molecular structure aswell as each of the individual isomeric forms of formula (I) and theirN-oxides, salts or solvates, substantially free, i.e. associated withless than 10%, preferably less than 5%, in particular less than 2% andmost preferably less than 1% of the other isomers. Thus, when a compoundof formula (I) is for instance specified as (E), this means that thecompound is substantially free of the (Z) isomer.

In particular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E (entgegen) or Z (zusammen)-stereochemistry at saiddouble bond. The terms cis, trans, R, S, E and Z are well known to aperson skilled in the art.

Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

Following CAS-nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R* ] or [R*,S*], where the first R* is alwaysspecified as the reference center and [R*,R*] indicates centers with thesame chirality and [R *,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the molecule has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “α” and “β” are used : the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system relative to the position of the highest prioritysubstituent on the reference atom is denominated “α”, if it is on thesame side of the mean plane determined by the ring system, or “β”, if itis on the other side of the mean plane determined by the ring system.

The compounds of (I) may be synthesized in the form of racemic mixturesof enantiomers which can be separated from one another followingart-known resolution procedures. The racemic compounds of formula (I)may be converted into the corresponding diastereomeric salt forms byreaction with a suitable chiral acid. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali.An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography using a chiralstationary phase. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

Whenever used hereinafter, the term “compounds of formula (I)” or anysubgroup thereof, is meant to also include their N-oxide forms, theirsalts, their stereochemically isomeric forms and their solvates. Ofspecial interest are those compounds of formula (I) which arestereochemically pure.

A first embodiment of the present invention are those compounds offormula (I) having the following formula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —C(═O)—; —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;    —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)p-; —C(═S)—; —NR^(x)—C(═S)—;    —Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—; —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—;-   Z¹ represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl;-   Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—C(═O)—; —NR^(x)—C(═O)—O—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; —C(═O)—Z²—O—;    —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;    —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;    —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;    —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—;-   Z² represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z² may optionally be replaced by    C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; aryl¹; aryl¹C₁₋₆alkyl;    Het¹; or Het¹C₁₋₆alkyl; provided that when Y represents    —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also    represent hydrogen;-   R² represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said    C₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,    1,3-benzodioxolyl may optionally be substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently selected from hydroxyl;    carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted    with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₄alkyl)amino; —S(═O)_(p)-C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—;    Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁ ₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; amino carbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi-or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy    optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;    polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl;    mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;    mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with aryl-C(═O)—;    hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono-or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or    di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   p represents 1 or 2;

provided that is excluded; a N-oxide thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof.

A second embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein X represents —C(═O)—C(═O)—; —O—C(═O)—;—NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—;—NR^(x)—C(═O)—Z¹—; —S(═O)p-; —NR^(x)—C(═S)—; in particular X represents—NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—;—NR^(x)—C(═O)—Z¹—; —S(═O)p-; —NR^(x)—C(═S)—; more in particular Xrepresents —NR^(x)—C(═O)—; —Z¹—C(═O)—; —C(═O)—Z¹—; —Z¹—NR^(x)—C(═O)—;—NR^(x)—C(═S)— or —S(═O)p-; even more in particular X represents—NR^(x)—C(═O)— or —Z¹—NR^(x)—C(═O)—; even more in particular—NR^(x)—C(═O)—.

A third embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein A represents N.

A fourth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein A represents CH, in particular wherein A representsCH and the dotted line does not represent a bond.

A fifth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein R¹ represents C₃₋₆cycloalkyl; adamantanyl; aryl¹;aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl;aryl¹; in particulararyl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; more in particular aryl¹;aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl, wherein said aryl¹ or Het¹represent phenyl, naphthalenyl, morpholinyl, piperidinyl, piperazinyl,pyrrolidinyl, furanyl, imidazolyl, thienyl, pyridyl; each of said cyclesrepresenting aryl¹ or Het¹ being optionally substituted with one or twosubstituents; in particular with aryl, C₁₋₆alkyl, arylC₁₋₄alkyl,hydroxyl, halo, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, nitro,C₁₋₆alkyloxycarbonyl, —S(═O)₂—C₁₋₄alkyl; more in particular with aryl,C₁₋₆alkyl, arylC₁₋₄alkyl, halo, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,—S(═O)₂—C₁₋₄alkyl. More in particular R¹ represents aryl¹ wherein aryl¹represents preferably optionally substituted phenyl. Even more inparticular R¹ represents phenyl substituted with C₁₋₆alkyloxy, e.g.methoxy.

A sixth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein R¹ represents C₁₋₁₂alkyl optionally substituted withcyano, C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;C₂₋₆alkenyl; C₂₋₆alkynyl; provided that when Y represents—NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;—C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may alsorepresent hydrogen.

A seventh embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein R² represents C₁₋₁₂alkyl; in particular C₁₋₆alkyl.

An eighth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein R² represents C₁₋₆alkyl or R³; in particular whereinR² represents R³ and said R³ represents phenyl, naphthalenyl,2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle containing 1or 2 N atoms, each of said cycles, in particular phenyl, beingoptionally substituted with one to five substituents, said substituentsbeing in particular halo, C₁₋₆alkyl optionally substituted with hydroxy,polyhaloC₁₋₆alkyl, C₁₋₆alkylthio, polyhaloC₁₋₆alkyloxy, carboxyl,hydroxyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, nitro,R⁵R⁴N—C(═O)—, R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl, Het-C(═O)—C₁₋₄alkyl,Het-C(═O)—; said substituents being more in particular halo, C₁₋₆alkyloptionally substituted with hydroxy, polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkyloxy, carboxyl, hydroxyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxycarbonyl, nitro,R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl; more in particular wherein R² representsphenyl substituted with one, two or three substituents, preferably threesubstituents, each substituent being selected from halo, e.g. chloro, orHetC₁₋₄alkyl, e.g. pyrrolidinylmethyl.

A ninth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein the compound of formula (I) is a compound of formula(I′)

wherein R^(3a) and R^(3a) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c)represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;—S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl;aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het;HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—.

A tenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein the compound of formula (I) is a compound of formula(I″)

wherein R^(3a) and R^(3a) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c)represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;—S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl;aryl; aryloxy; aryl-C(═O)—C₁₋₄alkyl; arylC₁₋₄alkyl; aryl-C(═O)—; Het;HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—.

A eleventh embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein the compound of formula (I) is a compound of formula(I′) or (I″) and wherein R^(3a) and R^(3b) each independently representhalo, C₁₋₆alkyl or C₁₋₆alkyloxy; in particular halo or C₁₋₆alkyl; morein particular both R^(3a) and R^(3b) represent halo, more in particularboth R^(3a) and R^(3b) represent chloro.

A twelfth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein the compound of formula (I) is a compound of formula(I′) or (I″) and wherein R^(3c) represents amino; mono-ordi(C₁₋₄alkyl)amino; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; Het-C(═O)—;Het-C(═O)—C₁₋₄alkyl or HetC₁₋₄alkyl; or R^(3c) represents hydrogen; morein particular wherein R^(3c) represents amino; mono-ordi(C₁₋₄alkyl)amino; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; Het-C(═O)— orHetC₁₋₄alkyl; or R^(3c) represents hydrogen; even more in particularwherein R^(3c) represents HetC₁₋₄alkyl, e.g. pyrrolidinylmethyl.

A thirteenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein p represents 2.

A fourteenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein Y represents —NR^(x)—C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;—NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;—NR^(x)—C(═O)—O—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—O—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—;—C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;—C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;—C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;—C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; or wherein Y representsNR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;—NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—C(═O)—O—;—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—;—C(═O)—Z²—; or wherein Y represents NR^(x)—C(═O)—Z²— or—NR^(x)—C(═O)—Z²—NR^(y); or wherein Y represents—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O— or —NR^(x)—C(═O)—Z²—C(═O)—O—. More inparticular Y represents —NR^(x)—C(═O)—Z²—.

A fifteenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein Y represents NR^(x)—C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—; —NR^(x)—C(═O)—Z²—O—;—NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—;—C(═O)—Z²—; —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—.

A sixteenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein Z² represents C₁₋₆alkanediyl or C₂₋₆alkenediyl; inparticular C₁₋₆alkanediyl; more in particular methylene.

A seventeenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein Z¹ represents C₁₋₆alkanediyl, optionally substitutedwith hydroxyl or amino, or wherein two hydrogen atoms attached to thesame carbon atom in C₁₋₆alkanediyl may optionally be replaced byC₁₋₆alkanediyl; in particular wherein Z¹ represents C₁₋₆alkanediyl.

An eighteenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein R^(x) represents hydrogen.

A nineteenth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein R^(y) represents hydrogen or C₁₋₄alkyl or C₂₋₄alkenylor —S(═O)_(p)-aryl.

A twentieth embodiment of the present invention are those compounds offormula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein R⁸ represents hydrogen.

A twenty first embodiment of the present invention are those compoundsof formula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein R⁸ represents halo, C₁₋₄alkyl or C₁₋₄alkylsubstituted with hydroxyl.

A twenty second embodiment of the present invention are those compoundsof formula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein aryl represents phenyl or phenyl substituted with oneor two substituents, preferably each substituent independently selectedfrom halo, C₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl or nitro.

A twenty third embodiment of the present invention are those compoundsof formula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein Het¹ represents a monocyclic non-aromatic or aromaticheterocycle or a bicyclic non-aromatic heterocycle, each of said cyclesmay optionally be substituted. In particular Het¹ representsmorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl,furanyl, imidazolyl, thienyl, pyridyl, 1,3-benzodioxolyl,tetrahydropyranyl, each of said heterocycles optionally beingsubstituted with one or two substituents, preferably each substituentindependently being selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,—S(═O)_(p)—C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, polyhaloC₁₋₆alkyl,C₁₋₆alkyloxy, nitro; more preferably each substituent independentlybeing selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,—S(═O)_(p)—C₁₋₄alkyl, aryl, arylC₁₋₄alkyl.

A twenty fourth embodiment of the present invention are those compoundsof formula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein aryl¹ represents phenyl, naphthalenyl or phenylsubstituted with one or two substituents, preferably each substituentindependently being selected from hydroxyl, halo, C₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl or Het.

A twenty fifth embodiment of the present invention are those compoundsof formula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein Het is a monocyclic non-aromatic or aromaticheterocycle, each of said heterocycles may optionally be substituted. Inparticular, Het is piperidinyl, pyrrolidinyl, piperazinyl, pyridyl,morpholinyl, each of said heterocycles optionally being substituted withone substituent, preferably the substituent is selected from C₁₋₆alkyl,C₁₋₆alkyl substituted with C₁₋₄alkyloxy, —S(═O)_(p)—C₁₋₄alkyl,C₁₋₆alkylcarbonyl.

A twenty sixth embodiment of the present invention are those compoundsof formula (I) or any subgroup thereof as mentioned hereinbefore asembodiment wherein one or more, preferably all, of the followingrestrictions apply:

-   a) X represents —NR^(x)—C(═O)—; —Z′—C(═O)—; —Z¹—NR^(x)—C(═O)—;    —C(═O)—Z¹—; —S(═O)p-; —NR^(x)—C(═S)—;-   b) R² represents C₁₋₆alkyl or R³, with R³ representing phenyl,    naphthalenyl or 1,3-benzodioxolyl, each of said cycles being    optionally substituted with one to five substituents, said    substituents being in particular halo, C₁₋₆alkyl optionally    substituted with hydroxy, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    carboxyl, hydroxyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,    C₁₋₆alkyloxycarbonyl, nitro, R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl.-   c) A represents N;-   d) A represents CH;-   e) Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—;-   f) Z¹ represents C₁₋₆alkanediyl optionally substituted with hydroxy;-   g) R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   h) aryl¹ represents phenyl, said phenyl optionally substituted with    C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, nitro,    C₁₋₆alkyloxycarbonyl;-   i) Het¹ represents a 5—Or 6-membered non-aromatic or aromatic    heterocycle, such as for example morpholinyl, piperidinyl,    piperazinyl, pyrrolidinyl, furanyl, imidazolyl, thienyl, pyridyl,    said 5- or 6-membered heterocycle optionally substituted with aryl,    C₁₋₆alkyl, arylC₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, —S(═O)₂—C₁₋₄alkyl.

A twenty seventh embodiment of the present invention are those compoundsof formula (I) having the following formula

wherein one or more, preferably all, of the following restrictionsapply:

-   a) A represents CH or N;-   b) X represents —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—;    —Z′—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —S(═O)p—; —NR^(x)—C(═S)—;-   c) Z¹ represents C₁₋₆alkanediyl; wherein said C₁₋₆alkanediyl may    optionally be substituted with hydroxyl or amino; and wherein two    hydrogen atoms attached to the same carbon atom in C₁₋₆alkanediyl    may optionally be replaced by C₁₋₆alkanediyl;-   d) Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—;    —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—;-   e) Z² represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z² may optionally be replaced by    C₁₋₆alkanediyl;-   f) R^(x) represents hydrogen or C₁₋₄alkyl;-   g) R^(y) represents hydrogen; C₁₋₄alkyl; C₂₋₄alkenyl; or    —S(═O)_(p)-aryl;-   h) R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹; Het¹;    or Het¹C₁₋₆alkyl; provided that when Y represents —NR^(x)—C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also    represent hydrogen;-   i) R² represents C₁₋₁₂alkyl or R³;-   j) R³ represents phenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or a    6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein    said phenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or 6-membered    aromatic heterocycle containing 1 or 2 N atoms may optionally be    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    selected from hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally    substituted with hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy;    C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;    C₁₋₆alkylcarbonyl; nitro; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl;    HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—;-   k) R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; Het-C₁₋₄alkyl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   l) R⁵ represents hydrogen or C₁₋₄alkyl;-   m) R⁶ represents C₁₋₄alkyl or C₁₋₄alkylcarbonyl;-   n) R⁷ represents hydrogen or C₁₋₄alkyl; or-   o) R⁶ and R⁷ may be taken together with the nitrogen to which they    are attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms each    independently selected from O or N;-   p) R⁸ represents hydrogen, halo, C₁₋₄alkyl substituted with    hydroxyl;-   q) aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one or two substituents, each substituent    independently being selected from halo; C₁₋₆alkyl;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; nitro;-   r) aryl¹ represents phenyl or naphthalenyl; wherein phenyl may    optionally be substituted with one or two substituents, each    substituent independently being selected from hydroxyl; halo;    C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl or Het;-   s) Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N, in particular N; said monocyclic heterocycle    optionally being substituted with one substituent, said substituent    being selected from C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylcarbonyl or —S(═O)_(p)—C₁₋₄alkyl;-   t) Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N, in particular N, O or S; or a bicyclic    non-aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N, in particular O;    said monocyclic heterocycle or said bicyclic heterocycle optionally    being substituted with one or two substituents, each substituent    independently being selected from halo; C₁₋₆alkyl;    C₁₋₆alkyloxy-carbonyl; —S(═O)_(p)—C₁₋₄alkyl; aryl; or arylC₁₋₄alkyl;-   u) p represents 2.

Preferred compounds of formula (I) are selected from

a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof

Preferably, preferred compounds of formula (I) are selected from

a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof

The compounds of formula (I) can be prepared according to the followingprocedures.

If not indicated, the skilled man will recognize in the below procedureswhen R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl, or R² representsR³, or R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl or R³.

In general, compounds of formula (I) wherein Y comprisesNR^(x)—C(═O)—Z²—, said compounds being represented by formula (I-a),wherein Y¹ represents the remainder of the linker Y including a directbond, can be prepared by reacting an intermediate of formula (II) withan intermediate of formula (III) in the presence of a suitabledehydrating (coupling) agent, such as for exampleN-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride(EDCI), dicyclohexylcarbodiimide (DCC), carbonyl diimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-Oxide(HBTU), 1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-) 3-Oxide (HCTU),O-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU) ordiethyl cyanophosphonate (DECP), optionally combined with hydroxybenzotriazole or chloro hydroxybenzotriazole, in the presence of asuitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine. This reaction ofan intermediate of formula (II) with an intermediate of formula (III)can also be performed in the presence of a suitable activating agent,such as for example Cl—C(═O)—C(═O)—Cl, a suitable base, such as forexample N,N-diethyl-ethanamine, and a suitable solvent, such as forexample N,N-dimethylformamide

The above reaction can be performed as a fast synthesis reaction therebyusing appropriate reagents well-known for fast synthesis, such as forexample dicyclohexylcarbodiimide (DCC) linked to an appropriate carrier,e.g. polystyrene. Also for the purification of the reaction mixture,appropriate fast-synthesis reagents can be used, such as for example1-ethenyl-4-(isocyanatomethyl)-benzene polymer with ethenylbenzene.

Compounds of formula (I-a) can also be prepared by reacting anintermediate of formula (II) with an intermediate of formula (IV)wherein W₁ represents a suitable leaving group, such as for examplehalo, e.g. chloro and the like, in the presence of a suitable base, suchas for example sodium hydride, sodium bicarbonate,N,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine, and a suitablesolvent, such as for example N,N-dimethylformamide, dichloromethane,acetonitrile or tetrahydrofuran

Compounds of formula (I) wherein Y represents —NR^(x)—C(═O)—Z²—NR^(y)—,said compounds being represented by formula (I-a-1), can be prepared byreacting an intermediate of formula (V) wherein W₂ represents a suitableleaving group, such as for example halo, e.g. chloro, bromo and thelike, with an intermediate of formula (VI) in the presence of a suitablebase, such as for example Na₂CO₃, K₂CO₃, and a suitable solvent, such asfor example N,N-dimethylformamide.

Compounds of formula (I) wherein Y represents —NR^(x)—C(═O)—Z²— and R¹represents an optionally substituted monocyclic saturated heterocyclelinked with a nitrogen atom to Z², said R¹ being represented by R^(1a),and said compounds being represented by formula (I-a-2), can be preparedby reacting an intermediate of formula (V) with an intermediate offormula (VII) in the presence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine, and a suitablesolvent, such as for example acetonitrile or tetrahydrofuran.

Compounds of formula (I) wherein R¹ is substituted with NH₂, said R¹being represented by R^(1′)—NH₂, and said compounds being represented byformula (I-b), can be prepared by deprotecting an intermediate offormula (VIII) wherein P represents a suitable protecting group, such asfor example tertiair butyloxycarbonyl, in the presence of a suitableacid, such as for example trifluoroacteic acid, and in the presence of asuitable solvent, such as for example dichloromethane. The intermediateof formula (VIII) can be prepared according to one of the abovereactions.

Compounds of formula (I) wherein X represents —X₁—NH—C(═O)— with X₁representing a direct bond or Z¹, said compounds being represented byformula (I-c), can be prepared by reacting an intermediate of formula(IX) with an intermediate of formula (X) in the presence of a suitablesolvent, such as for example acetonitrile, N,N-dimethylformamide ordichloromethane, optionally in the presence of a suitable base, such asfor example N,N-diethyl-ethanamine. Intermediates of formula (IX) arecommercially available or can be prepared by reacting R²—X₁—NH₂ withphosgene in the presence of a suitable solvent, such as for exampletoluene or acetonitrile, optionally in the presence of a suitable acid,such as for example hydrochloric acid.

The above reaction can also be performed as a fast synthesis reactionthereby using appropriate reagents well-known for fast synthesis, suchas for example for the purification of the reaction mixture1-ethenyl-4-(isocyanatomethyl)-benzene polymer with ethenylbenzene andtris-2-aminoethylamine linked to polystyrene can be used.

Compounds of formula (I-c) wherein X₁ represents a direct bond, saidcompounds being represented by formula (I-c-1), can be prepared byreacting an intermediate of formula (XXI) with Cl₃COC(═O)—Cl or C(═O)Cl₂optionally in the presence of HCl in diethylether, and in the presenceof a suitable solvent, such as for example acetonitrile or toluene,followed by reaction with an intermediate of formula (X) in the presenceof a suitable solvent, such as for example acetonitrile,N,N-dimethylformamide or dichloromethane, optionally in the presence ofa suitable base, such as for example N,N-diethyl-ethanamine orN,N-diisopropyl-ethanamine.

Compounds of formula (I) wherein X represents —X₁—C(═O)— with X₁representing a direct bond or Z¹, said compounds being represented byformula (I-d), can be prepared by reacting an intermediate of formula(XI) with an intermediate of formula (X) in the presence of a suitabledehydrating (coupling) agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, in the presence ofa suitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine. This reaction ofan intermediate of formula (XI) with an intermediate of formula (X) canalso be performed in the presence of a suitable activating agent, suchas for example Cl—C(═O)—C(═O)—Cl, a suitable base, such as for exampleN,N-diethyl-ethanamine, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein X represents —S(═O)_(p)—, saidcompounds being represented by formula (I-e), can be prepared byreacting an intermediate of formula (XII) wherein W₃ represents asuitable leaving group, such as for example halo, e.g. chloro and thelike, with an intermediate of formula (X) in the presence of a suitablebase, such as for example N,N-diisopropyl-ethanamine orN,N-diethyl-ethanamine, and a suitable solvent, such as for exampledichloromethane.

Compounds of formula (I) wherein X represents C(═O), said compoundsbeing represented by formula (I-f), can be prepared by reacting anintermediate of formula (XIII) wherein W₄ represents a suitable leavinggroup, such as for example halo, e.g. chloro and the like, with anintermediate of formula (X) in the presence of a suitable base, such asfor example N-methyl morpholine, and a suitable solvent, such as forexample N,N-dimethylformamide.

Compounds of formula (I) wherein X represents —C(═O)—Z₁—, said compoundsbeing represented by formula (I-g), can be prepared by reacting anintermediate of formula (XIV) with an intermediate of formula (X) in thepresence of a suitable solvent, such as for example an alcohol, e.g.ethanol.

Compounds of formula (I) wherein X represents X₁—NH—C(═S)— with X₁representing a direct bond or Z¹, said compounds being represented byformula (I-h), can be prepared by reacting an intermediate of formula(XV) with an intermediate of formula (X) in the presence of a suitablebase, such as for example N,N-diethyl-ethanamine, and a suitablesolvent, such as for example dichloromethane or tetrahydrofuran.

Compounds of formula (I) wherein R² represents R³, said R³ beingsubstituted with R⁵R⁴N—C₁₋₆alkyl, said R² being represented byR^(3′)—C₁₋₆alkyl-NR⁴R⁵ and said compounds being represented by formula(I-i), can be prepared by reacting an intermediate of formula (XVI)wherein W₅ represents a suitable leaving group, such as for exampleCH₃—S(═O)₂—O—, with NHR⁴R⁵ in the presence of a suitable solvent, suchas for example acetonitrile. Intermediates of formula (XVI) can beprepared by reacting the corresponding OH derivatives with CH₃—S(═O)₂—Clin the presence of a suitable base, such as for example pyridine, and asuitable solvent, such as for example dichloromethane.

Compounds of formula (I) wherein Y represents —C(═O)—NR^(x)—Y², whereinY² represents the remainder of the Y linker and said compounds beingrepresented by formula (I-j), can be prepared by reacting anintermediate of formula (XXXIV) with an intermediate of formula (XXXV)in the presence of DECP, a suitable base, such as for exampleN,N-diethyl-ethanamine or N,N-diisopropyl-ethanamine, and a suitablesolvent, such as for example dichloromethane or acetonitrile.

Compounds of formula (I) wherein R⁸ represents C₁₋₄alkyl substitutedwith hydroxyl, said compounds being represented by formula (I-k), can beprepared by reacting an intermediate of formula (XXXVI) with anappropriate acid, such as for example HCl and the like, in the presenceof a suitable solvent, such as for example an alcohol, e.g. 2-propanol.

Compounds of formula (I) wherein X contains Z¹, said Z¹ beingsubstituted with amino, said X being represented by Z¹(NH₂)—X₂, whereinX₂ represents the remainder of the linker X, and said compounds beingrepresented by formula (I-l), can be prepared by deprotecting anintermediate of formula (XXXVII) wherein P represents a suitable leavinggroup, such as for example tert butoxycarbonyl, with a suitable acid,such as for example trifluoroacetic acid, in the presence of a suitablesolvent, such as for example dichloromethane.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I) wherein R¹ or R² is unsubstituted, can beconverted into a compound wherein R¹ or R² contain aC₁₋₄alkyl-S(═O)_(p)— substituent, by reaction withC₁₋₄alkyl-S(═O)_(p)—W₆ wherein W₆ represents a suitable leaving group,such as for example halo, e.g. chloro and the like, in the presence of asuitable base, such as for example N,N-diethyl-ethanamine, and in thepresence of a suitable solvent, such as for example acetonitrile.

Compounds of formula (I) wherein R¹ or R² contains aC₁₋₆alkyloxycarbonyl substituent, can be converted into a compound offormula (I) wherein R¹ or R² contain a carboxyl substituent, by reactionwith a suitable base, such as for example sodium hydroxide, in thepresence of a suitable solvent, such as for example dioxane.

Compounds of formula (I) wherein R¹ or R² contain a C₁₋₆alkyloxycarbonylsubstituent, can also be converted into a compound of formula (I)wherein R¹ or R² contain a CH₂—OH substituent, by reaction with asuitable reducing agent, such as for example LiBH, in the presence of asuitable solvent, such as for example tetrahydrofuran or dioxane.

Compounds of formula (I) wherein R¹ or R² contain a C₁₋₆alkyloxycarbonylsubstituent, can also be converted into a compound of formula (I)wherein R¹ or R² are unsubstituted by reaction with a suitable acid,such as for example hydrochloric acid and the like.

Compounds of formula (I) wherein R¹ or R² contain a C₁₋₅alkyl-carbonylsubstituent, can be converted into a compound of formula (I) wherein R¹or R² contain a C₁₋₅alkyl-CH(OH)— substituent, by reaction with asuitable reducing agent, such as for example NaBH₄, in the presence of asuitable solvent, such as for example an alcohol, e.g. methanol.

Compounds of formula (I) wherein R¹ or R² contain a C₁₋₆alkyloxysubstituent, can be converted into a compound of formula (I) wherein R¹or R² contain a OH substituent, by reaction with a suitable reducingagent, such as for example BBr₃, in the presence of a suitable solvent,such as for example dichloromethane or dichloroethane.

Compounds of formula (I) wherein R¹ or R² contain a carboxylsubstituent, can be converted into a compound of formula (I) wherein R¹or R² contain a Het-C(═O)— substituent wherein Het represents anoptionally substituted monocyclic saturated heterocycle containing atleast one N atom, said heterocycle being linked via the N atom to theC(═O) group, by reaction with said heterocycle in the presence asuitable dehydrating (coupling) agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU), 1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-) 3-oxide (HCTU),O-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU) ordiethyl cyanophosphonate (DECP), optionally combined with hydroxybenzotriazole or chloro hydroxybenzotriazole, in the presence of asuitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine. This reaction canalso be performed as a fast synthesis reaction thereby using appropriatereagents well-known for fast synthesis, such as for exampledicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI), linked toan appropriate carrier, e.g. polystyrene. Also for the purification ofthe reaction mixture, appropriate fast-synthesis reagents can be used,such as for example 1-ethenyl-4-(isocyanatomethyl)-benzene polymer withethenylbenzene.

Compounds of formula (I) wherein R^(y) represents allyl, can beconverted into a compound of formula (I) wherein R^(y) representshydrogen, by reaction with a suitable catalyst, such as for examplePd(PPh₃)₄, and a suitable nucleophilic agent, such as for example

in the presence of a suitable solvent, such as for exampledichloroethane.

Compounds of formula (I) wherein R^(y) represents —S(═O)_(p)-arylwherein aryl is nitro-substituted phenyl, can be converted into acompound of formula (I) wherein R^(y) represents hydrogen, by reactionwith LiOH and HS—CH₂—C(═O)—OH in the presence of a suitable solvent,such as for example N,N-dimethylformamide.

The compounds of formula (I) and some of the intermediates in thepresent invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, chiral liquid chromatography and the like methods.Enantiomers can be obtained from racemic mixtures by first convertingsaid racemic mixtures with suitable resolving agents such as, forexample, chiral acids, to mixtures of diastereomeric salts or compounds;then physically separating said mixtures of diastereomeric salts orcompounds by, for example, selective crystallization or chromatographictechniques, e.g. liquid chromatography and the like methods; and finallyconverting said separated diastereomeric salts or compounds into thecorresponding enantiomers. Pure stereochemically isomeric forms may alsobe obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography or SCF (Super Critical Fluid) chromatography, inparticular using a chiral stationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

Intermediates of formula (II) wherein X represents —X₁—NH—C(═O)— with X₁representing a direct bond or Z¹, said intermediates being representedby formula (II-a), can be prepared by reacting an intermediate offormula (IX) with an intermediate of formula (XVII) wherein P representsa suitable protecting group, such as for example tertiairbutyloxycarbonyl, in the presence of a suitable solvent, such as forexample dichloromethane, followed by deprotecting the resultingintermediate of formula (XVIII) in the presence of a suitable acid, suchas for example trifluoroacetic acid, and in the presence of a suitablesolvent, such as for example dichloromethane. Before performing thedeprotection reaction, the intermediate of formula (XVIII) canoptionally be converted into an intermediate of formula (XVIII′) byreaction with C₁₋₄alkyl halide, e.g. CH₃I, in the presence of a suitablebase, such as for example NaH, and a suitable solvent, such as forexample N,N-dimethylformamide.

Intermediates of formula (II-a) wherein R^(x) represents hydrogen, saidintermediates being represented by formula (II-a-1), can be prepared byreacting an intermediate of formula (IX) with an intermediate of formula(IXX) in the presence of a suitable solvent, such as for exampledichloromethane, followed by hydrogenating (H₂ or N₂H₄.H₂O) theresulting intermediate of formula (XX) in the presence of a suitablecatalyst, such as for example platinum on charcoal or raney nickel,optionally a suitable catalyst poison, such as for example a thiophenesolution, and a suitable solvent, such as for example tetrahydrofuran oran alcohol, e.g. methanol. Before performing the hydrogenation reaction,the intermediate of formula (XX) can optionally be converted into anintermediate of formula (XX′) by reaction with C₁₋₄alkyl halide, e.g.CH₃I, in the presence of a suitable base, such as for example NaH, and asuitable solvent, such as for example N,N-dimethylformamide.

Intermediates of formula (II-a) wherein R^(x) represents hydrogen andwherein X₁ represents a direct bond, said intermediates beingrepresented by formula (II-a-2), can be prepared by reacting anintermediate of formula (XXI) with Cl₃COC(═O)—Cl followed by reactionwith an intermediate of formula (IXX) in the presence of a suitablebase, such as for example N,N-diethyl-ethanamine, and a suitablesolvent, such as for example toluene, followed by hydrogenating (H₂ orN₂H₄.H₂O) the resulting intermediate of formula (XXII) in the presenceof a suitable catalyst, such as for example platinum on charcoal orraney nickel, optionally a suitable catalyst poison, such as for examplea thiophene solution, and a suitable solvent, such as for exampletetrahydrofuran or an alcohol, e.g. methanol. Before performing thehydrogenation reaction, the intermediate of formula (XXII) canoptionally be converted into an intermediate of formula (XXII′) byreaction with C₁₋₄alkyl halide, e.g. CH₃I, in the presence of a suitablebase, such as for example NaH, and a suitable solvent, such as forexample N,N-dimethylformamide.

Intermediates of formula (II) wherein X represents —O—C(═O)—, saidintermediates being represented by formula (II-b), can be prepared byreacting an intermediate of formula (LII) with an intermediate offormula (LIII) wherein W₃ represents a suitable leaving group, such asfor example halo, e.g. chloro, in the presence of NaH, and a suitablesolvent, such as for example tetrahydrofuran, followed by hydrogenatingthe resulting product of formula (LIV) in a next step in the presence ofH₂, a suitable catalyst, such as for example platina on charcoal, asuitable catalyst poison, such as for example thiophene, and a suitablesolvent, such as for example acetic acid.

Intermediates of formula (V) can be prepared by reacting an intermediateof formula (II) with an intermediate of formula (XOH) wherein W₇represents a suitable leaving group, such as for example halo, e.g.chloro, bromo and the like, in the presence of a suitable base, such asfor example N,N-diethyl-ethanamine, N,N-diisopropyl-ethanamine and asuitable solvent, such as for example dichloromethane orN,N-dimethylformamide.

Intermediates of formula (X) wherein Y comprises NH—C(═O)—Z²—, saidintermediates being represented by formula (X-a), wherein Y¹ representsthe remainder of the linker Y including a direct bond, can be preparedaccording to the following reaction scheme wherein an intermediate offormula (XXIV) wherein P represents a suitable protecting group, such asfor example benzyloxycarbonyl or tertiair butyloxy or benzyl, andwherein W₈ represents a suitable leaving group, such as for examplehalo, e.g. chloro and the like, with an intermediate of formula (IXX) inthe presence of a suitable base, such as for example NaHCO₃, and asuitable solvent, such as for example dichloromethane, resulting in anintermediate of formula (XXV), followed in a next step by hydrogenating(H₂) said intermediate of formula (XXV) in the presence of a suitablecatalyst, such as for example platinum on charcoal, and a suitablesolvent, such as for example tetrahydrofuran, and an alcohol, e.g.methanol, resulting in an intermediate of formula (XXVI). In a nextstep, said intermediate of formula (XXVI) is reacted with anintermediate of formula (IV) in the presence of a suitable base, such asfor example NaHCO₃, and a suitable solvent, such as for exampleacetonitrile, resulting in an intermediate of formula (XXVII), which isdeprotected in a next step in the presence of H₂, a suitable catalyst,such as for example palladium on charcoal, and a suitable solvent, suchas for example an alcohol, e.g. methanol, and optionally in the presenceof a suitable acid, such as for example methanesulfonic acid; or in thepresence of a suitable acid, such as for example trifluoroacteic acid,and a suitable solvent, such as for example dichloromethane; or in thepresence of ammonium formate, a suitable catalyst, such as for examplepalladium on charcoal, and a suitable solvent, such as for example analcohol, e.g. methanol.

In the above reaction scheme, the intermediate of formula (XXVI) canalso react with an intermediate of formula (III) in the presence of asuitable activating agent, such as for example SOCl₂ orCl—C(═O)—C(═O)—Cl, a suitable base, such as for exampleN,N-diethyl-ethanamine or N,N-diisopropyl-ethanamine, and a suitablesolvent, such as for example dichloromethane or N,N-dimethylformamide.Or an intermediate of formula (III) can react with an intermediate offormula (XXVI) in the presence of a suitable dehydrating (coupling)agent, such as for exampleN-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride(EDCI), dicyclohexylcarbodiimide (DCC), carbonyl diimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU), 1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-) 3-oxide (HCTU),O-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU) ordiethyl cyanophosphonate (DECP), optionally combined with hydroxybenzotriazole or chloro hydroxybenzotriazole, in the presence of asuitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine.

The intermediate of formula (XXVII) can also react with an C₁₋₄alkylhalide, e.g. CH₃I, in the presence of a suitable base, such as forexample NaH, and a suitable solvent, such as for exampleN,N-dimethylformamide, to form an intermediate of formula (XXVIII) whichcan be deprotected according to the above described protocol to resultin an intermediate of formula (X-a′).

Intermediates of formula (X) wherein Y represents —C(═O)—NR^(x)—Z²—Y¹—,with Y¹ as defined hereinabove, said intermediates being represented bformula (X-b) can be prepared by deprotecting an intermediate of formula(XLIV) wherein P represents a suitable leaving group, such as forexample tertiair butyloxycarbonyl or benzyl, in the presence of asuitable acid, such as for example HCl or trifluoroacetic acid and thelike, and a suitable solvent, such as for example an alcohol, e.g.isopropanol, or dichloromethane, or in the presence of H₂, and asuitable catalyst, such as for example palladium on charcoal, and asuitable solvent, such as for example an alcohol, e.g. methanol.Intermediates of formula (XLIV) can be prepared by reacting anintermediate of formula (XLV) with an intermediate of formula (XLVI) inthe presence of a suitable dehydrating (coupling) agent, such as forexample N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU), 1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-) 3-oxide (HCTU),O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU) ordiethyl cyanophosphonate (DECP), optionally combined with hydroxybenzotriazole or chloro hydroxybenzotriazole, in the presence of asuitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine.

Intermediates of formula (III) can be prepared by hydrolizing anintermediate of formula (IXXX) with a suitable base, such as for examplepotassium hydroxide or sodium hydroxide, in the presence of a suitablesolvent, such as for example water, tetrahydrofuran or an alcohol. e.g.methanol.

Intermediates of formula (IXXX) wherein R¹ represents Het¹ wherein saidHet¹ is an optionally substituted heterocycle further substituted witheither optionally substituted phenyl or an optionally substitutedheterocycle, can be prepared by reacting the protected optionallysubstituted heterocycle with optionally substituted phenyl in thepresence of a suitable catalyst, such as for example palladium acetate,in the presence of a suitable catalyst ligand, such as for example1,1′-(1,5-pentanediyl)bis[1,1′-diphenylphosphine], a suitable base, suchas for example potassium acetate, and a suitable solvent, such as forexample N-methyl-pyrrolidin-2-one; or

-   by reacting the protected optionally substituted heterocycle with    optionally substituted phenyl carrying a suitable leaving group,    such as for example halo, e.g. bromo, iodo and the like, in the    presence of a suitable catalyst, such as for example palladium    acetate, in the presence of a suitable catalyst ligand, such as for    example 1,3-propanediylbis[diphenylphosphine], a suitable base, such    as for example potassium acetate or cesium carbonate, and a suitable    solvent, such as for example N-methyl-pyrrolidin-2-one; or-   by reacting the protected optionally substituted heterocycle with an    optionally substituted heterocycle carrying a suitable leaving    group, such as for example halo, e.g. bromo, iodo and the like, in    the presence of a suitable catalyst, such as for example palladium    acetate, in the presence of a suitable catalyst ligand, such as for    example 1,3-propanediylbis[diphenylphosphine], a suitable base, such    as for example potassium acetate or cesium carbonate, and a suitable    solvent, such as for example N-methyl-pyrrolidin-2-one.

Intermediates of formula (IXXX) wherein R¹ represents an optionallysubstituted phenyl further substituted with either optionallysubstituted phenyl or an optionally substituted heterocycle, can beprepared accordingly.

Intermediates of formula (IXXX) wherein Y¹ contains a NR^(y) whereinR^(y) represents C₂₋₄alkenyl, can be prepared from the correspondingintermediate wherein R^(y) represents hydrogen, by reaction withC₂₋₄alkenyl-W₉ wherein W₉ represents a suitable leaving group, such asfor example halo, e.g. iodo and the like, in the presence of a suitablebase, such as for example K₂CO₃ or N,N-diisopropyl-ethanamine, and asuitable solvent, such as for example N,N-dimethylformamide or analcohol, e.g. ethanol.

Intermediates of formula (IXXX) wherein Y¹ contains a NR^(y) whereinR^(y) represents —S(═O)_(p)-aryl, can be prepared from the correspondingintermediate wherein R^(y) represents hydrogen, by reaction withW₁₀—S(═O)_(p)-aryl wherein W₁₀ represents a suitable leaving group, suchas for example halo, e.g. chloro and the like, in the presence of asuitable base, such as for example N,N-diethyl-ethanamine, and asuitable solvent, such as for example acetonitrile.

Intermediates of formula (III) wherein Y¹ represents—NR^(y)—C(═O)—NR^(y)—, said intermediates being represented by formula(III-a), can be prepared by reacting an intermediate of formula (XXX)with an intermediate of formula (XXXI) in the presence of a suitablebase, such as for example N,N-diethyl-ethanamine, and a suitablesolvent, such as for example acetonitrile, followed by deprotecting theresulting intermediate of formula (XXXII) with a suitable base, such asfor example KOH, in the presence of a suitable solvent, such as forexample water and an alcohol, e.g. ethanol.

Intermediates of formula (IX) wherein X₁ represents a direct bond and R²contains a Het-C₁₋₄alkyl substituent, wherein Het represents amonocyclic, saturated N containing heterocycle represented by formula(XXXVIII), said intermediate of formula (IX) being represented byformula (IX-a), can be prepared by reacting an intermediate of formula(XXXVIII) with an intermediate of formula (XXXIX) in the represence of asuitable dehydrating (coupling) agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU), 1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-) 3-oxide (HCTU),O-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU) ordiethyl cyanophosphonate (DECP), optionally combined with hydroxybenzotriazole or chloro hydroxybenzotriazole, in the presence of asuitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine. The resultingintermediate of formula (XL) can then be reduced in a next step in thepresence of a suitable reducing agent, such as for example borane, inthe presence of a suitable solvent, such as for example tetrahydrofuran,to an intermediate of formula (XLI), which can then be converted into anintermediate of formula (IX-a) with phosgene in the presence of HCl indiethylether and a suitable solvent, such as for example toluene oracetonitrile.

Intermediates of formula (XL) can also be converted into an intermediateof formula (IX-b) with phosgene in the presence of HCl in diethyletherand a suitable solvent, such as for example toluene or acetonitrile ordichloromethane.

Intermediates of formula (IX-a) can also be prepared by reacting anintermediate of formula (XXXVIII) with an intermediate of formula (XLXI)wherein W₄ represents a suitable leaving group, such as for examplehalo, e.g. chloro and the like, in the presence of a suitable solvent,such as for example acetonitrile, resulting in an intermediate offormula (XLI′) with can be converted into an intermediate of formula(IX-a) as described hereinabove for intermediate (XLI).

Intermediates of formula (XXXIV) wherein X represents —X₁—HN—C(═O)—,said intermediates being represented by formula (XXXIV-a), can beprepared by hydrolysis of an intermediate of formula (XLII) in thepresence of a suitable base, such as for example sodium hydroxide, inthe presence of a suitable solvent, such as for example dioxane andoptionally an alcohol, e.g. methanol. Intermediates of formula (XLII)can be prepared by reacting an intermediate of formula (IX) with anintermediate of formula (XLIII) in the presence of a suitable base, suchas for example N,N-diethyl-ethanamine, and a suitable solvent, such asfor example dichloromethane.

Intermediates of formula (XXXIV) wherein X represents —X₁—C(═O)—, saidintermediates being represented by formula (XXXIV-b), can be prepared byhydrolysis of an intermediate of formula (XLII-a) in the presence of asuitable base, such as for example sodium hydroxide, in the presence ofa suitable solvent, such as for example dioxane and optionally analcohol, e.g. methanol. Intermediates of formula (XLII-a) can beprepared by reacting an intermediate of formula (XI) with anintermediate of formula (XLIII) in the presence of a suitabledehydrating (coupling) agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU), 1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-) 3-oxide (HCTU),O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU) ordiethyl cyanophosphonate (DECP), optionally combined with hydroxybenzotriazole or chloro hydroxybenzotriazole, in the presence of asuitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine.

Intermediates of formula (XI) can be prepared by hydrolysis of anintermediate of formula (XLVII) in the presence of LiOH, an acid, suchas for example HCl, and a suitable solvent, such as for example analcohol, e.g. methanol. Intermediates of formula (XLVII) wherein R²contains Het-C₁₋₄alkyl as substituent, said intermediates beingrepresented by formula (XLVII-a) can be prepared by reacting anintermediate of formula (XLVIII) wherein W₅ represents a suitableleaving group, such as for example halo, e.g. bromo and the like, withan intermediate of formula (XXXVIII).

Intermediates of formula (XLVIII-a) as depicted below, can be preparedby reacting an intermediate of formula (XLIX) with N-bromosuccinimide inthe presence of 2,2′-(1,2-diazenediyl)bis[2-methylpropanenitrile] and asuitable solvent, such as for example CCl₄. Intermediates of formula(XLIX) wherein X₁ represents CH₂, said intermediates being representedby formula (XLIX-a), can be prepared by reacting an intermediate offormula (XLX) with sodium metal, in the presence of a suitableC₁₋₄alkyl-OH, followed by adding a suitable acid, such as for examplesulfuric acid. Intermediates of formula (XLX) can be prepared byreacting an intermediate of formula (XXI-a) with1,1-dimethylethyl-nitrous acid ester, CuCl₂, 1,1-dichloroethene in asuitable solvent, such as for example acetonitrile.

Intermediates of formula (XXXVI-a) can be prepared according to thefollowing reaction scheme. In a first step, an intermediate of formulaLV wherein W₁₁ represents a suitable leaving group, such as for examplefluoro, is reacted with 3,4-dihydro-2H-pyran in the presence of4-methyl-benzenesulfonic acid and a suitable solvent, such as forexample dichloromethane, resulting in an intermediate of formula (LVI).Said intermediate is in a next step reacted with an intermediate offormula (LVII) wherein P represents a suitable protecting group, such asfor example benzyl, in the presence of Na₂CO₃ and a suitable solvent,such as for example N,N-dimethylformamide resulting in an intermediateof formula (LVIII). In a next step, said intermediate is hydrogenatedwith H₂ in the presence of a suitable catalyst, such as for exampleplatinum on charcoal, a catalyst poison, such as for example thiophene,and a suitable solvent, such as for example tetrahydrofuran, resultingin an intermediate of formula (LIX). This intermediate is then reactedwith an intermediate of formula (III) in the presence of a suitabledehydrating (coupling) agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide(HBTU),1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyltetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, in the presence ofa suitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine. This reaction ofan intermediate of formula (LIX) with an intermediate of formula (III)can also be performed in the presence of a suitable activating agent,such as for example Cl—C(═O)—C(═O)—Cl, a suitable base, such as forexample N,N-diethyl-ethanamine, and a suitable solvent, such as forexample N,N-dimethylformamide. This reaction can be performed as a fastsynthesis reaction thereby using appropriate reagents well-known forfast synthesis, such as for example dicyclohexylcarbodiimide (DCC)linked to an appropriate carrier, e.g. polystyrene. Also for thepurification of the reaction mixture, appropriate fast-synthesisreagents can be used, such as for example1-ethenyl-4-(isocyanatomethyl)-benzene polymer with ethenylbenzene. In anext step, the intermediate of formula (LX) is deprotected with H₂, inthe presence of a suitable catalyst, such as for example palladium oncharcoal, a suitable base, such as for example N,N-diethyl-ethanamine,and a suitable solvent, such as for example tetrahydrofuran resulting inan intermediate of formula (LXI) which can in a next step be reactedwith an intermediate of formula (IX) in the presence of a suitablesolvent, such as for example dichloromethane, to obtain an intermediateof formula (XXXVI-a).

Intermediates of formula (XXXVII-a) can be prepared by reacting anintermediate of formula (XI) wherein X₁ is substituted with a protected(P, such as for example tertiair butyloxycarbonyl) amino group, saidintermediate being represented by formula (XI-a), with an intermediateof formula (X) in the presence of a suitable dehydrating (coupling)agent, such as for exampleN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI),1-[bis(di-methylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide (HBTU),1-[bis(dimethyl-amino)methylene]-5-chloro-1H-benzotriazolium-hexafluorophosphate(1-)3-oxide (HCTU), O-benzotriazolyl tetramethylisouronium tetrafluoroborate(TBTU) or diethyl cyanophosphonate (DECP), optionally combined withhydroxy benzotriazole or chloro hydroxybenzotriazole, in the presence ofa suitable solvent, such as for example N,N-dimethylformamide,dichloromethane, acetonitrile or tetrahydrofuran, and optionally in thepresence of a suitable base, such as for exampleN,N-diisopropyl-ethanamine or N,N-diethyl-ethanamine.

Intermediates of formula (XI) wherein X₁ represents CHOH, saidintermediates being represented by formula (XI-b) can be prepared byreacting an intermediate of formula (LXII) in the presence of ZnBr₂,Si(CH₃)₃—CN and an acid, such as for example HCl, in the presence of asuitable solvent, such as for example dichloromethane. Intermediates offormula (LXII) can be prepared by reacting an intermediate of formula(LXIII) wherein W₁₂ represents a suitable leaving group, such as forexample halo, e.g. bromo and the like, with N,N-dimethylformamide in thepresence of BuLi and a suitable solvent, such as for exampletetrahydrofuran.

Pharmacological Part

As already indicated above, the present invention relates to the use ofa DGAT inhibitor, in particular a DGAT1 inhibitor, to elevate levels ofone or more satiety hormones, in particular GLP-1 levels. The presentinvention also relates to the use of a DGAT inhibitor, in particular aDGAT1 inhibitor, for the manufacture of a medicament for the preventionor the treatment, in particular for the treatment, of a disease whichcan benefit from an elevated level of one or more satiety hormones, inparticular a disease which can benefit from an elevated GLP-1 level. Inparticular, GLP-1 levels are elevated in plasma or in portal blood, morein particular in plasma. By elevated GLP-1 levels, e.g. elevated GLP-1plasma level or an elevated GLP-1 level in portal blood, it is meantthat the GLP-1 level of a subject having taken a DGAT1 inhibitor iselevated or increased compared to the subject under the same conditionsbut not having taken the DGAT1 inhibitor. In particular GLP-1 levels areelevated in fasting conditions or postprandial, more in particularpostprandial.

Therapeutic uses for a compound which elevates GLP-1 level include, butare not limited to, improving learning, enhancing neuro-protection,and/or alleviating a symptom of a disease or disorder of the centralnervous system, e.g., through modulation of neurogenesis, and e.g.,Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, ALS,stroke, hemorrhage, cerebrovascular accident, ADD, and neuropsychiatricsyndromes; converting liver stem/progenitor cells into functionalpancreatic cells; preventing beta-cell deterioration and stimulation ofbeta-cell proliferation; treating pancreatitis; treating obesity;suppressing appetite and inducing satiety; treating irritable bowelsyndrome or inflammatory bowel disease such as Crohn's disease andulcerative colitis; reducing the morbidity and/or mortality associatedwith myocardial infarction and stroke; treating acute coronary syndromecharacterized by an absence of Q-wave myocardial infarction; attenuatingpost-surgical catabolic changes; treating hibernating myocardium ordiabetic cardiomyopathy; suppressing plasma blood levels ofnorepinepherine; increasing urinary sodium excretion, decreasing urinarypotassium concentration; treating conditions or disorders associatedwith toxic hypervolemia, e.g., renal failure, congestive heart failure,nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension;inducing an inotropic response and increasing cardiac contractility;treating polycystic ovary syndrome; treating respiratory distress;improving nutrition via a non-alimentary route, i.e., via intravenous,subcutaneous, intramuscular, peritoneal, or other injection or infusion;treating nephropathy; treating left ventricular systolic dysfunction,e.g., with abnormal left ventricular ejection fraction; inhibitingantro-duodenal motility, e.g., for the treatment or prevention ofgastrointestinal disorders such as diarrhea, postoperative dumpingsyndrome and irritable bowel syndrome, and as premedication inendoscopic procedures; treating critical illness polyneuropathy (CIPN)and systemic inflammatory response syndrome (SIRS); modulatingtriglyceride levels and treating dyslipidemia; treating organ tissueinjury (e.g. brain tissue injury) caused by reperfusion of blood flowfollowing ischemia; improving the function of ischemic and reperfusedbrain tissue; treating coronary heart disease risk factor (CHDRF)syndrome. Further diseases which can benefit from an elevated GLP-1level, include, but are not limited to, ischemic myocardial stunning;ishemic/reperfusion injury; acute myocardial infarction; leftventricular dysfunction; vascular disease; neuropathy, includingperiphere sensoric neuropathy associated with type II diabetes;bone-related disorders, including osteoporosis, obesity, diabetes.Because of the effect on GLP-1, the DGAT inhibitors can also be used toprovide cardioprotection.

References supporting the above indications include ExperimentalNeurology, Vol. 203(2), pp 293-301 (2007); U.S. Pat. No. 7,186,683; J.Pharm. Exp. Ther. vol. 312, No. 1, pp 303-308 (2005); Diabetes, vol. 54,pp 146-151 (2005); US2007/0021339, which are incorporated herein byreference.

In view of the DGAT inhibitory activity, in particular the DGAT1inhibitory activity, the present compounds of formula (I), their N-oxideforms, their pharmaceutically acceptable salts or their solvates, can beused as a medicine. In particular, the present invention relates to acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof for use as a medicine, inparticular for use as a medicine for the prevention or the treatment ofa disease which can benefit from an elevated GLP-1 level. In particular,the present invention also relates to the use of a compound of formula(I) for the manufacture of a medicament for the prevention or thetreatment of a disease which can benefit from an elevated GLP-1 level,such as the diseases and disorders mentioned above.

In view of the above-described utility for a DGAT inhibitor, inparticular a DGAT1 inhibitor, there is provided a method of treating awarm-blooded mammal, including a human, suffering from or a method ofpreventing a warm-blooded mammal, including a human, to suffer from adisease which can benefit from an elevated level of GLP-1, in particulara method of treating a warm-blooded mammal, including a human, sufferingfrom a disease which can benefit from an elevated level of GLP-1. Saidmethods comprise the administration of an effective amount of a DGATinhibitor, in particular a DGAT1 inhibitor, to a warm-blooded mammal,including a human.

In view of the DGAT inhibitory activity of the compounds of formula (I),there is provided a method of treating a warm-blooded mammal, includinga human, suffering from or a method of preventing a warm-blooded mammal,including a human, to suffer from a disease which can benefit from anelevated level of GLP-1, in particular a method of treating awarm-blooded mammal, including a human, suffering from a disease whichcan benefit from an elevated level of GLP-1. Said methods comprise theadministration of an effective amount of a compound of formula (I), aN-oxide form thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, to a warm-blooded mammal, including a human.

In view of the DGAT inhibitory activity, in particular the DGAT1inhibitory activity, the present invention also relates to a compound offormula (I), a N-oxide form thereof, a pharmaceutically acceptable saltthereof or a solvate thereof for use as a medicine, in particular foruse as a medicine for the prevention or the treatment of a diseaseswhich can benefit from inhibition of DGAT, in particular DGAT1. Theinvention also relates to the use of a compound of formula (I), aN-oxide form thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, for the manufacture of a medicament for the preventionor the treatment of a disease or disorder which can benefit frominhibition of DGAT, in particular DGAT1. Diseases or disorders which canbenefit from inhibition of DGAT, in particular DGAT1 include, but arenot limited to metabolic disorders, such as obesity and obesity relateddisorders (including peripheral vascular disease, cardiac failure,myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes,in particular type II diabetes mellitus, and complications arisingtherefrom (such as retinopathy, neuropathy, nephropathy), syndrome X,insulin resistance, impaired glucose tolerance, conditions of impairedfasting glucose, hypoglycemia, hyperglycemia, hyperuricemia,hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia,dyslipidemia, mixed dyslipidemia, hypertriglyceridemia and nonalcoholicfatty liver disease, fatty liver, increased mesenteric fat,non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis,ketosis, dysmetabolic syndrome; dermatological conditions such as acne,psoriasis; cardiovascular diseases, such as atherosclerosis,arteriosclerosis, acute heart failure, congestive heart failure,coronary artery disease, cardiomyopathy, myocardial infarction, anginapectoris, hypertension, hypotension, stroke, ischemia, ischemicreperfusion injury, aneurysm, restenosis and vascular stenosis;neoplastic diseases, such as solid tumors, skin cancer, melanoma,lymphoma and endothelial cancers, e.g., breast cancer, lung cancer,colorectal cancer, stomach cancer, other cancers of the gastrointestinaltract (e.g., esophageal cancer and pancreatic cancer), prostate cancer,kidney cancer, liver cancer, bladder cancer, cervical cancer, uterinecancer, testicular cancer and ovarian cancer; and other diseases andconditions that are sensitive or responsive to modulation, in particularinhibition, of DGAT function, in particular DGAT1 function.

Particular diseases or disorders which can benefit from inhibition ofDGAT, in particular DGAT1, are selected from obesity,hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia,hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease,liver fibrosis, non-alcoholic steatohepatitis and diabetes, inparticular type II diabetes.

In view of the DGAT inhibitory activity of the compounds of formula (I),there is provided a method of treating a warm-blooded mammal, includinga human, suffering from or a method of preventing a warm-blooded mammal,including a human, to suffer from a disease which can benefit frominhibition of DGAT, in particular a method of treating a warm-bloodedmammal, including a human, suffering from a disease which can benefitfrom inhibition of DGAT. Said methods comprise the administration of aneffective amount of a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, to awarm-blooded mammal, including a human.

The present invention also provides compositions for preventing ortreating a disease which can benefit from an elevated GLP-1 level orwhich can benefit from inhibition of

DGAT, in particular DGAT1, in particular for treating a disease whichcan benefit from elevated GLP-1 levels or which can benefit frominhibition of DGAT, in particular DGAT1. Said compositions comprise atherapeutically effective amount of a compound of formula (I), a N-oxideform thereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and a pharmaceutically acceptable carrier.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs. To prepare the pharmaceuticalcompositions of this invention, an effective amount of the particularcompound, optionally in salt form, as the active ingredient is combinedin intimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable,particularly, for administration orally, rectally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs,emulsions and solutions; or solid carriers such as starches, sugars,kaolin, diluents, lubricants, binders, disintegrating agents and thelike in the case of powders, pills, capsules, and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit forms, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. Also included are solid form preparations, whichare intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

The compounds of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

The compounds of the present invention may also be topicallyadministered in the form of drops, in particular eye drops. Said eyedrops may be in the form of a solution or a suspension. Any systemdeveloped for the delivery of solutions or suspensions as eye drops aresuitable for the administration of the present compounds.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of formula (I), and, from 1 to 99.95% by weight,more preferably from 30 to 99.9% by weight, even more preferably from 50to 99.9% by weight of a pharmaceutically acceptable carrier, allpercentages being based on the total weight of the composition.

In view of the above described effects of DGAT inhibitors and/or theeffect on GLP-1 levels by DGAT inhibitors, the present invention alsorelates to

-   a) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and a dipeptidyl peptidase-4 inhibitor (DPP-4    inhibitor).

DPP-4 is a membrane-spanning cell surface aminopeptidase widelyexpressed in many tissues, such as liver, lung, kidney, intestinalbrush-border membranes, lymphocytes, endothelial cells. DPP-4 cleavespeptides with a proline or alanine residue in the second aminoterminalposition. Many gastro-intestinal hormones are substrates for DPP-4,among them GLP-1. A DPP-4 inhibitor thus inhibits cleavage of GLP-1 andhence provides for an increase in the level of GLP-1. Therefore, acombination as indicated above can be used to combine the activity ofthe DGAT inhibitor and the DPP4 inhibitor in order to elevate GLP-1levels. By administering a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof, with a DPP4 inhibitor, different mechanisms may be targeted inorder to achieve elevated levels of GLP-1. In this way, the use of sucha combination may reduce the dosage of the DGAT inhibitor and the DPP4inhibitor required for a desired elevation in GLP-1 level as compared towhen the DGAT inhibitor or the DPP4 inhibitor is administered as amonotherapy. Therefore, these combinations may reduce or eliminate sideeffects of monotherapy while not interfering with the GLP-1 levelincreasing activity. Also, the combination of a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and a DPP4 inhibitor can be used as a medicine.The present invention also relates to a product comprising (a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) a DPP4 inhibitor,as a combined preparation for simultaneous, separate or sequential usein the treatment of a disease which can benefit from an elevated levelof GLP-1. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or they may each be present in a separatepreparation together with pharmaceutically acceptable carriers. SaidDPP4 inhibitor which may be combined with a DGAT inhibitor according tothe present invention, in particular a DGAT1 inhibitor, may be a knownDPP4 inhibitor such as for example sitagliptin, vildagliptin, andsaxagliptin.

-   b) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and a GLP-1 analogue. Said GLP-1 analogue can be    considered as an agonist at the GLP-1 receptor.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and a GLP-1 analogue can be used as a medicine. The presentinvention also relates to a product containing (a) a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and (b) a GLP-1 analogue, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of a disease which can benefit from an elevated level ofGLP-1. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or they may each be present in a separatepreparation together with pharmaceutically acceptable carriers.

Said GLP-1 analogue which may be combined with a DGAT inhibitoraccording to the present invention may be a known GLP-1 analogue such asfor example exenatide, exenatide LAR or liraglutide.

-   c) a combination of a DGAT inhibitor, in particular a DGAT1    inhibitor, more in particular a compound of formula (I), a N-oxide    form thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof, and an anti-diabeticum.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an anti-diabeticum can be used as a medicine. The presentinvention also relates to a product containing (a) a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and (b) an anti-diabeticum, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of a disease which can benefit from an elevated level of GLP-1or DGAT inhibition, such as for example diabetes, in particular type IIdiabetes. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or they may each be present in a separatepreparation together with pharmaceutically acceptable carriers. Saidanti-diabeticum which may be combined with a DGAT inhibitor according tothe present invention may be a known anti-diabeticum such as for examplemetformin, glibenclamide, rosiglitazon, pioglitazon, repaglinide,glimepiride, acarbose, glicazide, glipizide, nateglinide, tolbutamide, aprotein tyrosine phosphatase 1 inhibitor, or a 11-beta-hydroxysteroiddehydrogenase inhibitor.

d) a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor,more in particular a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, and aphosphodiesterase (PDE) inhibitor, in particular a PDE10A or PDE11Ainhibitor. Phosphodiesterase (PDE) inhibitors, in particular PDE10A orPDE11A inhibitors, are known to be insulin secretagogues, and to enhancethe signalling of GLP-1 by inhibition of the hydrolysis of cAMP. Also,the combination of a DGAT inhibitor, in particular a DGAT1 inhibitor,more in particular a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, and aphosphodiesterase (PDE) inhibitor, in particular a PDE10A or PDE11Ainhibitor, can be used as a medicine. The present invention also relatesto a product containing (a) a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and (b) a phosphodiesterase (PDE) inhibitor, in particular aPDE10A or PDE11A inhibitor, as a combined preparation for simultaneous,separate or sequential use in the treatment of a disease which canbenefit from an elevated level of GLP-1 or DGAT inhibition, such as forexample diabetes, in particular type II diabetes, or obesity. Thedifferent drugs of such a combination or product may be combined in asingle preparation together with pharmaceutically acceptable carriers orthey may each be present in a separate preparation together withpharmaceutically acceptable carriers. Said phosphodiesterase (PDE)inhibitor, in particular a PDE10A or PDE11A inhibitor, which may becombined with a DGAT inhibitor according to the present invention may bea known PDE inhibitor such as for example papaverine, PQ-10,dipyridamole, ibudilast or tadalafil.

e) a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor,more in particular a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, and anappetite suppressant. Also, the combination of a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and an appetite suppressant can be used as amedicine. The present invention also relates to a product containing (a)a DGAT inhibitor, in particular a DGAT1 inhibitor, more in particular acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) an appetitesuppressant, as a combined preparation for simultaneous, separate orsequential use in the treatment of a disease which can benefit from anelevated level of GLP-1 or DGAT inhibition, such as for examplediabetes, in particular type II diabetes, or obesity. The differentdrugs of such a combination or product may be combined in a singlepreparation together with pharmaceutically acceptable carriers or theymay each be present in a separate preparation together withpharmaceutically acceptable carriers. Said appetite suppressants, whichmay be combined with a DGAT inhibitor according to the present inventionmay be a known appetite suppressant such as for example sibutramine andphentermine.

f) a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor,more in particular a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, and ananti-obesity drug with a CNS (central nervous system) mode of actionsuch as for example a CB1 antagonist or inverse agonists.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an anti-obesity drug with a CNS (central nervous system)mode of action can be used as a medicine. The present invention alsorelates to a product containing (a) a DGAT inhibitor, in particular aDGAT1 inhibitor, more in particular a compound of formula (I), a N-oxideform thereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and (b) an anti-obesity drug with a CNS (central nervoussystem) mode of action, as a combined preparation for simultaneous,separate or sequential use in the treatment of a disease which canbenefit from an elevated level of GLP-1 or DGAT inhibition, such as forexample diabetes, in particular type II diabetes, or obesity. Thedifferent drugs of such a combination or product may be combined in asingle preparation together with pharmaceutically acceptable carriers orthey may each be present in a separate preparation together withpharmaceutically acceptable carriers. Said anti-obesity drugs with a CNS(central nervous system) mode of action, which may be combined with aDGAT inhibitor according to the present invention may be a known aanti-obesity drug such as for example Rimonabant, orlistat, SLV-319, orMK-0364.

g) a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor,more in particular a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, and anhypolipidemic drug such as for example 3-hydroxy-3-methyl-glutarylcoenzyme A (HMG-CoA) reductase inhibitors, squalene synthase inhibitors,FXR (farnesoid X receptor) and LXR (liver X receptor) ligands,cholestyramine, fibrates, nicotinic acid and aspirin.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an hypolipidemic drug can be used as a medicine. Thepresent invention also relates to a product containing (a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) an hypolipidemicdrug, as a combined preparation for simultaneous, separate or sequentialuse in the treatment of a disease which can benefit from an elevatedlevel of GLP-1 or DGAT inhibition, such as for example diabetes, inparticular type II diabetes, or obesity. The different drugs of such acombination or product may be combined in a single preparation togetherwith pharmaceutically acceptable carriers or they may each be present ina separate preparation together with pharmaceutically acceptablecarriers. Said hypolipidemic drug which may be combined with a DGATinhibitor according to the present invention may be a knownhypolipidemic drug such as for example lovastatin, pravastatin,simvastatin, pravastatin, cerivastatin, mevastatin, velostatin,fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin.

h) a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor,more in particular a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, and anagonist of peroxisome proliferator-activator receptor such as forexample fenofibrate.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an agonist of peroxisome proliferator-activator receptorsuch as for example fenofibrate, can be used as a medicine. The presentinvention also relates to a product containing (a) a DGAT inhibitor, inparticular a DGAT1 inhibitor, more in particular a compound of formula(I), a N-oxide form thereof, a pharmaceutically acceptable salt thereofor a solvate thereof, and (b) an agonist of peroxisomeproliferator-activator receptor such as for example fenofibrate, as acombined preparation for simultaneous, separate or sequential use in thetreatment of a disease which can benefit from an elevated level of GLP-1or DGAT inhibition, such as for example diabetes, in particular type IIdiabetes, or obesity. The different drugs of such a combination orproduct may be combined in a single preparation together withpharmaceutically acceptable carriers or they may each be present in aseparate preparation together with pharmaceutically acceptable carriers.

i) a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor,more in particular a compound of formula (I), a N-oxide form thereof, apharmaceutically acceptable salt thereof or a solvate thereof, and anantihypertensive agent.

Also, the combination of a DGAT inhibitor, in particular a DGAT1inhibitor, more in particular a compound of formula (I), a N-oxide formthereof, a pharmaceutically acceptable salt thereof or a solvatethereof, and an antihypertensive agent, can be used as a medicine. Thepresent invention also relates to a product containing (a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of formula (I), a N-oxide form thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) anantihypertensive agent, as a combined preparation for simultaneous,separate or sequential use in the treatment of a disease which canbenefit from an elevated level of GLP-1 or DGAT inhibition, such as forexample diabetes, in particular type II diabetes, or obesity. Thedifferent drugs of such a combination or product may be combined in asingle preparation together with pharmaceutically acceptable carriers orthey may each be present in a separate preparation together withpharmaceutically acceptable carriers. Said anti-hypertensive agent whichmay be combined with a DGAT inhibitor according to the present inventionmay be a known anti-hypertensive agent, e g loop diuretics such asethacrynic acid, furosemide and torsemide, angiotensin converting enzyme(ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, moexipril, perinodopril, quinapril, ramipril andtrandolapril; inhibitors of the Na-K-ATPase membrane pump such asdigoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors suchas omapatrilat, sampatrilat and fasidotril; angiotensin II antagonistssuch as candesartan, eprosartan, irbesartan, losartan, telmisartan andvalsartan, in particular valsartan; renin inhibitors such as ditekiren,zankiren, terlakiren, aliskiren, RO 66-1132 and RO-66-1168; β-adrenergicreceptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol,metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agentssuch as digoxin, dobutamine and milrinone; calcium channel blockers suchas amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine,nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists;and aldosterone synthase inhibitors.

The following examples are intended to illustrate the present invention.

Experimental Part

Hereinafter, the term ‘m.p.” means melting point, ‘THF’ meanstetrahydrofuran, ‘EtOAc’ means ethyl acetate, ‘MeOH’ means methanol,‘HOBT’ means 1-hydroxy-1H-benzotriazole, ‘DIPE’ means diisopropyl ether,‘DMF’ means N,N-dimethylformamide, ‘Et₃N’ or ‘TEA’ means triethylamine,‘DPPENT’ means 1,1′-(1,5-pentanediyl)bis[1,1′-diphenylphosphine],“resin-linked-N═C═O” means a polystyrene based resin functionalized withicocyanato-groups such as for example1-ethenyl-4-(isocyanatomethyl)-benzene polymer with ethenylbenzene,“PS-Carbodiimide” means polystyrene resin-boundN-cyclohexylcarbodiimide, “DCM” means dichloromethane, “TBTU” means14bis(dimethylamino)methylene-1H-benzotriazoliumtetrafluoroborate(1-)3-oxide, “MP-carbonate” is macroporoustriethylammonium methylpolystyrene carbonate (a macroporous polystyreneanion-exchange resin that is a resin-bound equivalent oftetraalkylammonium carbonate), “DECP” means diethyl cyanophosphonate,“DIPEA” means diisopropylethylamine, “TFA” means trifluoro acetic acid,“NBS” means N-bromosuccinimide, “AIBN” means2,2′-azobis[isobutyronitrile] and “HBTU” means1-[bis(dimethylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide.

MiniBlock™ (Mettler Toledo) is a flexible, easy to use tool designed forparallel synthesis.

ArgoScoop™ resin (Biotage) dispenser is a variable volumn resin scoopdesigned for convenient dispensing of polymer scavengers and reagents.

For some compounds that were purified by reversed phase high-performanceliquid chromatography (HPLC) the used method is described below(indicated in the compound procedure with HPLC method A). Whennecessary, this method can be slightly adjusted by a person skilled inthe art to obtain a more optimal result for the separation.

HPLC Method A

The product was purified by reversed-phase high-performance liquidchromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8μm, 250 g, I.D. 5 cm). Two mobile phases were used (phase A: 90% of a0.5% NH₄OAc solution in water+10% CH₃CN; phase B: CH₃CN). First, 85% Aand 15% B with a flow rate of 40 ml/min was hold for 0.5 minutes. Then agradient was applied to 10% A and 90% B in 41 minutes with a flow rateof 80 ml/min. Then a gradient was applied to 100% B in 20 minutes with aflow rate of 80 ml/min and hold for 4 minutes.

A. Preparation of the Intermediates

Example A1

a. Preparation of Intermediate 1

A mixture of [4-(4-piperidinyl)phenyl]carbamic acid1,1-dimethylethylester (0.025 mol) in CH₂Cl₂ (100 ml) was stirred whilecooling on an ice-bath. A solution of 1,3-dichloro-2-isocyanatobenzene(0.027 mol) in CH₂Cl₂ (25 ml) was added dropwise. The reaction mixturewas allowed to warm to room temperature. The reaction mixture wasstirred for one hour at room temperature. The resulting precipitate wasfiltered off, washed with DIPE and dried. Yield: 6.2 g ofintermediate 1. The corresponding filtrate's solvent was evaporated. Theresidue was triturated under DIPE, filtered off and dried. Yield: 4.2 gof intermediate 1.

b. Preparation of Intermediate 2

A mixture of intermediate 1 (prepared according to A1.a) (0.022 mol) andtrifluoroacetic acid (25 ml) in CH₂Cl₂ (250 ml) was stirred for 2 hoursat room temperature. The solvent was evaporated. The residue wastriturated under DIPE, filtered off and dried. This fraction (11.2 g)was converted into the free base by adding aqueous ammonia. This mixturewas extracted with DCM. The separated organic layer was dried, filteredand the solvent evaporated. Yield: 7.6 g of intermediate 2.

c. Preparation of Intermediate 3

3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methylpropanoic acid (0.001mol) was dissolved in DMF (5 ml) to get stock solution (I). Part ofstock solution (I) (1.2 ml, containing 0.00024 mol of3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methylpropanoic acid was putinto the MiniBlock. PS-Carbodiimide, 1.9 mmol/g (0.0004 mol) was addedwith ArgoScoop. A solution of 1-hydroxy-M-benzotriazole (0.00030 mol) inDMF (1 ml) was added and the mixture was shaken for 30 minutes. Asolution of intermediate 2 (prepared according to A1.b) (0.0002 mol) inDMF (3.5 ml) was added and the reaction mixture was shaken overnight.MP-carbonate, 2.8 mmol/g (0.00090 mol) and resin-linked-N═C═O, 1.8mmol/g (0.0002 mol) were added with ArgoScoop. The reaction mixture wasshaken overnight, then filtered. DCM (4 ml) was added and the mixturewas shaken for 2 hours. The mixture was filtered and the filtrate'ssolvent was evaporated (Genevac). The residue was purified by HPLC. Theproduct fractions were collected and worked-up. Yield: 0.066 g ofintermediate 3 (S-enantiomer).

d. Preparation of Intermediate 25

A mixture of intermediate 2 (prepared according to A1.b) (0.00027 mol)and Et₃N (0.0004 mol) in CH₂Cl₂ (5 ml) was stirred and cooled on anice-bath. Bromoacetylchloride (0.00027 mol) was added dropwise. Thereaction mixture was stirred for one hour while cooling on the ice-bath.The solvent was evaporated. The residue was triturated under CH₃CN/DIPE.The precipitate was filtered off and dried, yielding intermediate 25(used as such in the next reaction step).

Example A2

a. Preparation of Intermediate 4

A mixture of 1-(4-nitrophenyl)-piperazine (0.02413 mol) in CH₂Cl₂ p.a.(100 ml) was stirred on an ice bath. Then1,3-dichloro-2-isocyanatobenzene (0.02660 mol) in DCM p.a. (20 ml) wasadded dropwise while the reaction mixture was stirred on the ice bath.For 2 hours, the reaction mixture was let to warm up to room temperatureand was stirred at room temperature. The reaction mixture was filteredoff and washed with DIPE (q.s.). The precipitate was dried in vacuo.Yield: 8.923 g of intermediate 4 (94%; yellow powder)

b. Preparation of Intermediate 5

A mixture of intermediate 4 (prepared according to A2.a) (0.047 mol) inCH₃OH (200 ml), THF (200 ml) and NH₃ in CH₃OH (100 ml) was stirred for15 minutes at room temperature and then hydrogenated at room temperature(atmospheric pressure) with Pt/C 5% (4 g) as a catalyst in the presenceof thiophene solution (3 ml; 4% in DIPE). After uptake of H₂ (3 equiv),the catalyst was filtered off (the product was also a precipitate andwas therefore dissolved by washing the filter residue with DCM). Thecombined filtrate ‘s solvent was evaporated. Yield: 14.616 g ofintermediate 5.

c. Preparation of Intermediate 26

Et₃N (1100 ml) was added to a solution of intermediate 5 (0.006023 mol)in DMF (20 ml). 2-bromoacetylbromide (0.007228 mol) was added dropwiseat stirring. The reaction mixture was stirred for 3 hours at roomtemperature, after that 50 ml of water was added. The formed precipitatewas filtered off and washed with water. Yield: 2.454 g of intermediate26 (84%) (light-green crystalline).

Example A3

a. Preparation of Intermediate 6

Trichloromethyl carbonochloridic acid ester (0.008 mol) was addeddropwise to a solution of 2-chloro-4,6-dimethoxybenzenaminehydrochloride (0.008 mol) and Et₃N (4.1 ml) in dry toluene (100 ml) atstirring. The reaction mixture was stirred at 60° C. for 2 hours tillthe starting aniline reacted completely (control by TLC). The solutionof 1-(4-nitrophenyl)piperazine (1.63 g; 0.008 mol) in DCM (25 ml) wasadded to the reaction mixture at 60° C. at stirring. The stirring wascontinued at 60-70° C. for 1 hour. Then, the reaction mixture wasconcentrated in vacuum. The formed yellow sediment was treated withwater and filtered off. Then, it was washed with water, ether and driedon air for 24 hours. Yield: 3.19 g of intermediate 6 (98%; yellowpowder).

b. Preparation of Intermediate 7

Small portions of Raney nickel were added to a solution of intermediate6 (0.00757 mol) and hydrazine.H₂O (3.5 ml) in methanol (170 ml) at 45°C. and stirring in such a way as to prevent the violent reaction. Whenthe reaction was completed (control by TLC) the catalyst was filteredoff and washed with hot methanol (50 ml) and chloroform (70 ml).Washings and filtrate were concentrated in vacuum. The residue wasdiluted in benzene and concentrated. This procedure was repeated twice.The final compound was triturated with hexane and filtered off. Yield:2.705 g of intermediate 7 (91%; dark crystalline powder).

Example A4

a. Preparation of Intermediate 8

A mixture of 1-(4-nitrophenyl)piperazine (0.244 mol) and NaHCO₃ (0.269mol) in CH₂Cl₂ (300 ml) was stirred on a cold-water bath. A solution ofphenylmethyl carbonochloridic acid ester (0.257 mol) in DCM (60 ml) wasadded dropwise over one hour. The reaction mixture was stirred furtherfor 20 hours. CH₃CN (50 ml) was added. Water (250 ml) was added. Themixture was stirred over the weekend. The layers were separated Theseparated organic layer was dried (MgSO₄), filtered and the solventevaporated, then co-evaporated with toluene. The residue was stirred inDIPE (250 ml), filtered off, washed, then dried (vacuum, 50° C.). Yield:77.5 g of intermediate 8 (93%).

b. Preparation of Intermediate 9

A mixture of intermediate 8 (0.23 mol) in CH₃OH (150 ml) and THF (150ml) was hydrogenated at 50° C. with Pt/C, 5% (5 g) as a catalyst. Afteruptake of H₂ (17 1), the catalyst was filtered off and the filtrate wasevaporated, then co-evaporated with toluene. The residue was trituratedunder DIPE (250 ml) and EtOAc (20 ml), then filtered off, washed withDIPE and dried in vacuo at 50° C. Yield: 54.9 g of intermediate 9 (77%).

c. Preparation of Intermediate 10

A mixture of intermediate 9 (0.115 mol) and NaHCO₃ (0.13 mol) in CH₃CN(400 ml) was stirred on a water-bath. A solution of benzenebutanoylchloride (0.12 mol) in CH₃CN (50 ml) was added dropwise. The reactionmixture was stirred further at room temperature for 3 days. The mixturewas poured out into water (2 l), then stirred for one hour. Theprecipitate was filtered off, washed with water, then recrystallizedfrom ethanol. The precipitate was filtered off, washed with ethanol, anddried (vacuum, 50° C.). Yield: 45.9 g of intermediate 10 (87%).

c-1. Preparation of Intermediate 37

A blood-red solution of 4-methoxybenzene acetic acid (1.000 g, 0.00602mol) and SOCl₂ (4.4 ml, 0.0602 mol) was stirred for 45 minutes at 60° C.The solution was evaporated and co-evaporated with toluene. The residuewas dissolved in DCM (10 ml) and the solution was cooled on an ice-bath.Then intermediate 9 (prepared according to A4.b) (1.875 g, 0.00602 mol)and N,N-diisopropyl-ethanamine (1.50 ml, 0.00903 mol) were added and thereaction mixture was stirred overnight at room temperature. The solutionwas treated with 5% citric acid (20 ml) and extracted twice with DCM.The combined organic layers were subsequently treated with 10% Na₂CO₃(20 ml), resulting in a suspension in the organic layer which wasseparated, evaporated and co-evaporated. Yield: 2.862 g of intermediate37 (off white solid; pure; m.p.: 173° C. (DSC method)).

d. Preparation of Intermediate 11

A solution of intermediate 10 (0.095 mol) in CH₃OH, p.a. (500 ml) washydrogenated in a Parr apparatus (8 pounds pressure) with Pd/C, 10% (5g) as a catalyst. After uptake of H₂ (1 equiv), the catalyst wasfiltered off and the filtrate was evaporated. Toluene was added andazeotroped on the rotary evaporator. The oily residue solidified uponstanding. Except for 1 g, the residue was dried at room temperature in adesiccator under pump vacuum. Yield: 30.4 g intermediate 11 (98.9%).

d-1. Preparation of Intermediate 38

A mixture of intermediate 37 (prepared according to A4.c-1) (2.35 g,0.00511 mol), Pd/C 10% (0.5 g), methanesulfonic acid (0.5 g, 0.00520mol), H₂ (q.s) and CH₃OH (50 ml) was hydrogenated overnight at roomtemperature. The product was worked-up. Yield: 1.982 g of intermediate38 (methanesulfonic acid salt) (m.p.: 202° C. (DSC method).

Example A5

a. Preparation of Intermediate 12

A mixture of benzenebutanoic acid (0.0113 mol) and SOCl₂ (1.17 ml) inCH₂Cl₂ (20 ml) was refluxed for 2 hours. The solvent was evaporated andco-evaporated 2 times with toluene. The residue was dissolved in CH₂Cl₂(20 ml). This mixture was added drop wise at room temperature in 20minutes to a solution of 4-(4-aminophenyl)-1-piperazinecarboxylic acid1,1-dimethylethyl ester (0.0094 mol) and Et₃N (1.8 ml) in CH₂Cl₂ (30 ml)and stirred for 91 hours at room temperature. The reaction mixture wasextracted with H₂O and then washed with Na₂CO₃ aqueous solution (10%).The separated organic layer was dried (MgSO₄), filtered and the solventwas evaporated. The residue was purified by reversed-phasehigh-performance liquid chromatography. (Shandon Hyperprep® C18 BDS(Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with thementioned mobile phases was applied (phase A: a 0.25% NH₄HCO₃ solutionin water; phase B: CH₃OH (optional); phase C: CH₃CN). The desiredproduct fractions were collected, the solvent was evaporated andco-evaporated with CH₃OH.

The residue was dissolved in H₂O. This mixture was extracted with DCM.The organic layer was dried (MgSO₄), filtered and the solvent wasevaporated. Yield: 2.012 g of intermediate 12.

b. Preparation of Intermediate 13

NaH 60% in paraffine (0.0016 mol) was added to a solution ofintermediate 12 (0.0014 mol) in DMF, dry (20 ml) and then stirred for 1hour at room temperature. CH₃I (0.0027 mol) was added to the reactionmixture and stirred for 21 hours. The solvent was evaporated. Theresidue was partitioned between H₂O and CH₂Cl₂. The separated organiclayer was dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by reversed-phase high-performance liquidchromatography. (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8μm, 250 g, I.D. 5 cm). A gradient with the mentioned mobile phases wasapplied (phase A: a 0.25% NH₄HCO₃ solution in water; phase B: CH₃OH(optional); phase C: CH₃CN). The product fractions were collected, thesolvent was evaporated and co-evaporated with CH₃OH/CH₃CN. Yield: 0.444g of intermediate 13

c. Preparation of Intermediate 14

CF₃COOH (0.550 ml) was added to a solution of intermediate 13 (0.0007mol) in CH₂Cl₂ (10 ml) and the mixture was stirred for 40 hours at roomtemperature. The reaction mixture was extracted with Na₂CO₃ aqueoussolution (10%). The separated organic layer was dried (MgSO₄), filteredand the solvent was evaporated. The residue was purified byreversed-phase high-performance liquid chromatography. (ShandonHyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). Agradient with the mentioned mobile phases was applied (phase A: a 0.25%NH₄HCO₃ solution in water; phase B: CH₃OH (optional); phase C: CH₃CN).The product fractions were collected and the solvent was evaporated.Yield: 0.200 g of intermediate 14.

Example A6

a. Preparation of Intermediate 15

A mixture of compounds N-methylglycine ethyl ester hydrochloride (7.00mmol) and Et₃N (1.033 ml) in acetonitrile (5 ml) was stirred for 20minutes at room temperature. Compound 2-isocyanatopropane (6.65 mmol)was added dropwise to the reaction mixture and stirring was continuedfor 5 hours at room temperature. Then the reaction mixture was dilutedwith DCM (20 ml) and washed with H₂O (10 ml). The organic layer wasseparated, dried over Na₂SO₄ and concentrated in vacuum. The residue waspurified by Flash-chromatography (eluent: ethyl acetate). Yield: 0.908 gof intermediate 15 (64%; yellowish oil).

b. Preparation of Intermediate 16

A solution of KOH (6 mmol)) in H₂O (3 ml) was added to a solution ofintermediate 15 (0.003 mol) in ethanol (3 ml). The reaction mixture wasstirred for 18 hours at room temperature. Then the reaction mixture wasdiluted with H₂O (20 ml) and extracted with DCM (5 ml). The aqueouslayer was separated, acidified with concentrated HCl to pH=3-4 andextracted with a mixture dichloromethane/ethanol—10/1 (3×5 ml). Combinedorganic extract was dried over Na₂SO₄ and concentrated in vacuum. Yield:0.275 g of intermediate 16 (58%; yellowish oil). It was used in the nextstep of the synthesis without additional purification.

c. Preparation of Intermediate 17

A mixture of intermediate 16 (0.002342 mol), EDCI (0.002253 mol), Et₃N(0.582 ml) in THF (20 ml) was stirred for 20 minutes at roomtemperature. Then compounds4-[4-(phenylmethyl)-1-piperazinyl]benzenamine (0.001802 mol) and HOBT(0.002253 mol) were added and stirring was continued for 24 hours atroom temperature. After that the solvent was evaporated in vacuum, theresidue was diluted with water (20 ml), and the formed precipitate wasfiltered off and washed with water. The washed precipitate was dissolvedin a mixture of DCM/ethanol—10/1 (50 ml). This solution was passedthrough silica gel on Shott's filter. The filtrate was evaporated invacuum. The residue was triturated with ethyl acetate. The precipitatewas filtered off and washed with ethyl acetate. Yield: 0.239 g ofintermediate 17 (31%).

d. Preparation of Intermediate 18

CH₃OH (10 ml) was added to a mixture of intermediate 17 (0.496 mmol),ammonium formate (1.983 mmol) and Pd/C 10% (0.106 g) under argon. Thereaction mixture was stirred for 2 hours at 50° C. The catalyst wasfiltered off and washed with methanol. Combined filtrate wasconcentrated in vacuum. The residue was dissolved in DCM (30 ml) andwashed with water (10 ml). The organic layer was separated, dried overNa₂SO₄ and concentrated in vacuum. The residue was triturated withwater; the obtained precipitate was filtered off, washed with water anddried on air. Yield: 0.091 g of intermediate 18 (55%).

Example A7

a. Preparation of Intermediate 19

[4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.09 mol) inCH₂Cl₂ (500 ml) and DMF (5 ml) was stirred. Ethanedioyl dichloride (0.09mol) was added dropwise. The mixture was stirred for 1 hour to givemixture 1. 4-[1-(phenylmethyl)-4-piperidinyl]-benzenamine.hydrochloride(0.046 mol) in CH₂Cl₂ (500 ml) and Et₃N (20 ml) was stirred on anice-bath to give mixture 2. Mixture 1 was added dropwise to mixture 2.The resulting mixture was stirred and refluxed overnight, then cooledand washed with water. The organic layer was separated, dried, filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: DCM/CH₃OH 98/2). The desiredproduct fractions were collected and the solvent was evaporated. Theresidue was triturated in DIPE. The precipitate was filtered off anddried. Yield: 5.6 g of intermediate 19.

b. Preparation of Intermediate 20

A mixture of intermediate 19 (prepared according to A7.a) (0.025 mol) inCH₃OH (250 ml) was hydrogenated at 50° C. overnight with Pd/C 10% (2 g)as a catalyst. After uptake of H₂ (1 equiv), the catalyst was filteredoff and the filtrate was evaporated. The residue was triturated in DIPE.The precipitate was filtered off and dried. Yield: 7.7 g of intermediate20 (73%).

Example A8

a. Preparation of Intermediate 21

A mixture of benzenebutanoic acid (0.0131 mol) and SOCl₂ (12 ml) wasrefluxed for 1 hour while stirring. The excess of SOCl₂ was removed invacuo. The residue was diluted with dry benzene (15 ml) and thenconcentrated (repeated twice). Then, a solution of acyl chloride inbenzene (10 ml) was added dropwise to a mixture of4-[4-(phenylmethyl)-1-piperazinyl]benzenamine (0.0094 mol), Et₃N (2.8ml) and dry benzene (45 ml) while stirring. The reaction mixture wasrefluxed for 3 hours at stirring. Sedimentation was observed. Thereaction mixture with formed precipitate was concentrated. Then, residuewas partitioned between DCM (60 ml) and 10% aqueous K₂CO₃ (40 ml). Theorganic layer was separated, washed with water, dried over MgSO₄, andconcentrated in vacuum. The residue was triturated with an ether-hexanemixture. The formed precipitate was filtered off and dried on air.Yield: 3.71 g of intermediate 21 (96%).

a-1. Preparation of Intermediate 22

Intermediate 22 was prepared according to A8.a except forbenzenebutanoic acid which should be replaced by 4-methoxybenzene aceticacid. Yield: 3.9 g (100%) of intermediate 22.

b. Preparation of Intermediate 23

Intermediate 21 (prepared according to A8.a) (0.0897 mol) was dissolvedin methanol (350 ml) and stirred for 1 hour under reflux (badsolubility). Then Pd/C 10% (0.6 g) and NH₄HCO₃ (4 g) were added to thereaction mixture. The resulting mixture was refluxed for 4 hours. Anadditional amount of Pd/C 10% (0.2 g) and NH₄HCO₃ (2 g) were added. Theresulting mixture was refluxed for 4 hours more. Then, the catalyst wasfiltered off on a paper filter. The filtrate was concentrated in vacuum.The residue was diluted with CH₂Cl₂ (100 ml) and washed with K₂CO₃ (50ml 10% solution). The organic layer was separated, washed with water,dried over MgSO₄, and concentrated in vacuum. Yield: 2.437 g (80%) ofintermediate 23 (greenish solid compound). (According to LC/MS theN-formyl derivative was found in the target product, approximately 7%).

c. Preparation of Intermediate 24

Intermediate 22 (0.0939 mol) (prepared according to A8.a-1) wasdissolved in methanol (350 ml) and stirred for 1 hour under reflux. ThenPd/C 10% (0.8 g) and NH₄HCO₃ (0.088 mol) were added to the reactionmixture. The resulting mixture was refluxed for 4 hours. The catalystwas filtered off by a paper filter. The filtrate was concentrated invacuum. The residue was diluted in DCM (100 ml) and washed with K₂CO₃(50 ml 10% solution). The organic layer was separated, washed withwater, dried over MgSO₄, and concentrated in vacuum. Yield: 2.503 g(81%) of crude intermediate 24 was obtained as a solid. According toLC/MS, the admixture of N-formyl derivative was found in the targetproduct (approximately 12%). The crude product was purified by columnchromatography on silica gel and eluted with acetone and then withmethanol. The appropriate eluent for the target product is the mixtureof MeOH/Et₃N (3/1). The desired fractions were collected and worked-up.Yield: 2.08 g (67%) of intermediate 24.

Example A9

a. Preparation of Intermediate 27

A mixture of intermediate 4 (prepared according to A2.a) (0.0025 mol)and NaH 60% (0.00030 mol) in DMF (50 ml; dried over 3 Å molecular sieve)was stirred for 25 minutes at room temperature. Then CH₃I (0.173 ml) wasadded to the reaction mixture. The reaction mixture was stirred for 45minutes and then again CH₃I (0.032 ml) was added. The reaction mixturewas stirred for 270 minutes. The solvent was evaporated. The residue waspurified by reversed-phase high-performance liquid chromatography.(Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D.5 cm). A gradient with the mentioned mobile phases was applied (phase A:a 0.25% NH₄HCO₃ solution in water; phase B: CH₃OH (optional); phase C:CH₃CN). The product fractions were collected and the solvent wasco-evaporated with toluene and CH₃CN. Yield: 0.410 g of intermediate 27(yellow powder)

b. Preparation of Intermediate 28

A mixture of intermediate 27 (prepared according to A9.a) (0.001 mol) inCH₃OH (25 ml) and THF (25 ml) was hydrogenated at room temperature withPt/C 5% (0.2 g) as a catalyst in the presence of thiophene solution (0.2ml; 4% in DIPE). After uptake of H₂ (3 equiv.), the catalyst wasfiltered off and the filtrate's solvent was evaporated. The residue wassuspended in DCM and then filtered again over Celite (Column wasprewashed with CH₃OH in order to remove small amounts of catalyst, stillpresent in the residue). The filtrate was evaporated. Yield: 0.376 g ofintermediate 28.

Example A10

Preparation of Intermediate 29

A solution of compound 29 (prepared according to B17) (0.0004 mol) inpyridine, p.a., dried on molecular sieves (3 ml) was stirred on anice-bath. A solution of methanesulfonyl chloride (0.0007 mol) in CH₂Cl₂,p.a. (0.5 ml) was added dropwise by means of a syringe. After addition,the reaction mixture was stirred further at 0° C. for 1 hour, and atroom temperature for 2 hours. The solvents were evaporated. Yield:intermediate 29. The residue was used as such.

Example A11

Preparation of Intermediate 30

A mixture of 5-chloro-2,3-dihydro-4-benzofuranamine (0.0019 mol) and 20%phosgene in toluene (3 ml) was reacted in a pressure vessell at 140° C.for 18 hours. During the heat-up phase the mixture started to become asolution. The reaction mixture was allowed to reach room temperature,and the volatiles were evaporated, and co-evaporated with toluene. Thecrude intermediate 30 was used as such in the next reaction step.

Example A12

a. Preparation of Intermediate 31

A mixture of N-(2-chlorophenyl)-β-alanine methyl ester (0.0137 mol),3-iodo-1-propene (0.042 mol), andN-ethyl-N-(1-methylethyl)-2-propanamine (6.90 ml) in DMF (15 ml) wasstirred for 6 hours at 60° C. Then the volatile matters were evaporatedunder reduced pressure at 95° C./30 mm Hg. The residue was treated witha mixture of DCM (20 ml) and K₂CO₃ (7% aqueous solution, 20 ml). Theorganic layer was separated, dried over MgSO₄, and the solvent wasremoved under reduced pressure. The residue was purified bychromatography (eluent: hexane/ethyl acetate—10/1). Yield: (84%) ofintermediate 31 (yellow oil).

b. Preparation of Intermediate 32

A solution of KOH (0.016 mol) in water (9 ml) was added to a solution ofintermediate 31 (0.0114 mol) in MeOH (60 ml). The reaction mixture wasstirred at room temperature for 5 hours. Then the solvent was evaporatedin vacuum to dryness. The residue was dissolved in MeOH (40 ml) andneutralized with concentrated HCl (d=1.19; V=1.30 ml). Precipitated KClwas removed by filtration and washed with MeOH (10 ml). The solvent fromfiltrate was removed under reduced pressure. The residue was purified bychromatography (eluent: CHCl₃/acetone—25/1). Yield: 1.954 g ofintermediate 32 (72%).

Example A13

a. Preparation of Intermediate 33

2-Nitrobenzenesulfonylchloride (0.0127 mol) was added to a solution ofN-(o-chlorobenzyl)-β-alanine methyl ester (0.0127 mol) in dioxane (10ml). The reaction mixture was stirred under reflux for 8 hours. When thereaction was over, the reaction mixture was diluted with water (100 ml)and extracted with CH₂Cl₂ (3×50 ml). The combined organic layers weredried over Na₂SO₄. The solvent was removed under reduced pressure. Thetarget product crystallized after addition of hexane. Yield: 3.627 g ofof intermediate 33 (94%; white crystalline powder).

b. Preparation of Intermediate 34

Concentrated HCl (7.00 ml) was added to a solution of intermediate 33(0.0117 mol) in dioxane (10 ml). The reaction mixture was stirred underreflux for 8 hours. When the reaction was over, the reaction mixture wasdiluted with water (100 ml) and extracted with DCM (3×50 ml). Combinedorganic extract was dried over Na₂SO₄. The solvent was removed underreduced pressure. The target product crystallized after addition ofhexane. Yield: 3.627 g of intermediate 34 (94%; white crystallinepowder).

Example A14

a. Preparation of Intermediate 35

A mixture of 2,4-dimethylbenzeneacetic acid (0.5 g, 0.003 mol), DCM (20ml) and

DMF (1 ml) was stirred at room temperature. SOCl₂ (1 ml) was added. Thereaction mixture was stirred and refluxed for 2 hours. The solvent wasevaporated (2×DCM). The residue was dissolved in DCM and this solutionwas added dropwise to a mixture of4-[4-(phenylmethyl)-1-piperazinyl]benzenamine (0.813 g, 0.003 mol), DCM(30 ml) and DIPEA (1.5 ml) at 10° C. The reaction mixture was stirredovernight at room temperature. Then H₂O was added and the mixture wasstirred for 15 minutes. The organic layer was separated, dried and thesolvent was evaporated. The residue was worked-up in DIPE. The solid wasfiltered off and dried. Yield: 0.780 g of intermediate 35.

b. Preparation of Intermediate 36

A mixture of intermediate 35 (0.0018 mol) in CH₃OH (50 ml) washydrogenated with Pd/C 10% (0.050 g) as a catalyst. After uptake of H₂(47 ml), the mixture was filtered over Dicalite. The solvent wasevaporated and the residue was crystallized from DIPE. The solid wasfiltered off and dried. Yield: 0.483 g of intermediate 36.

Example A15

a. Preparation of Intermediate 39

A solution of 4-amino-3,5-dichlorobenzoylchloride (0.0680 mol) inCH₂Cl₂, p.a. (100 ml) was added dropwise to a stirring solution ofpyrrolidine (14.8 ml; 0.18 mol) in CH₂Cl₂, p.a. (100 ml), while coolingon an ice-bath. After addition, the reaction mixture was stirred furtherat 0° C. for 1 hour. The reaction mixture was washed with H₂O (150 ml).The separated organic layer was dried with MgSO₄, filtered off,evaporated, and co-evaporated with toluene. The residue (19 g) wasfiltered over silica using CH₂Cl₂—CH₃OH 99/1 as eluent. The desiredfractions were combined and evaporated, and co-evaporated with toluene.Yield: 16.5 g of intermediate 39 (94%)

b. Preparation of Intermediate 40

A solution of intermediate 39 (prepared according to A15.a) (16.5 g;0.0636 mol) and borane-THF 1M in THF (175 ml) was stirred and refluxedfor 4 hours. The reaction mixture was allowed to reach room temperature,and more borane-THF 1M in THF (200 ml) was added, and the reactionmixture was stirred and refluxed further for 3 hours. The reactionmixture was allowed to reach room temperature, and poured slowly into 1Lstirring ice-water. Stirring was continued for 18 hours. NaHCO₃ (35 g)was added, and the resulting suspension was extracted with CH₂Cl₂. Theseparated organic layer was washed with H₂O, dried with MgSO₄, filteredoff, evaporated, and co-evaporated with toluene. The residue wastriturated in iPrOH (75 ml), and the solid was filtered off, washed with2×iPrOH, and to the filtrate was added HCl-iPrOH 6N (25 ml), and thesolvents were evaporated. The residue (10.5 g) was stirred with EtOAc(75 ml), and decanted. The residue was triturated with EtOAc (75 ml),filtered off, and washed with 2×EtOAc. The resulting solid on the filterwas dissolved in CH₂Cl₂+NaHCO₃ aqueous saturated solution, and theresulting biphasic solution was stirred for 30 minutes. The organiclayer was separated, dried with MgSO₄, filtered off, evaporated, andco-evaporated with toluene. Yield: 3.5 g of intermediate 40 (22%).

c. Preparation of Intermediate 41

HCl 1M in diethylether (4.9 ml; 0.0049 mol) was added to a stirringsolution of intermediate 40 (prepared according to A15.b) (0.57 g;0.0023 mol) in CH₃CN p.a. dried on molecular sieves (20 ml) under N₂flow. The reaction mixture was put on an ice-bath, and phosgene 20% intoluene (1.75 ml) was added. The reaction mixture was stirred further atroom temperature (ice-bath was removed immediately after addition) for18 hours. More phosgene 20% in toluene (0.6 ml) was added, and thereaction mixture was stirred further at room temperature for 65 hours.The crude intermediate 41 was used as such in the next reaction step.

d. Preparation of Intermediate 42

HCl 1M in Et₂O (10.32 ml; 0.0206 mol) was added to a stirring solutionof intermediate 40 (4.6 g; 0.0188 mol) in CH₃CN p.a. dried on molecularsieves (75 ml) and CH₂Cl₂ p.a (10 ml). Stirring was continued for 1hour. A precipitate was formed. The reaction mixture was cooled on anice-bath, and phosgene 20% in toluene (14 ml) was added. The reactionmixture was stirred further for 3 hours. Extra phosgene 20% in toluene(7 ml) was added, and the reaction mixture was stirred further at roomtemperature for 18 hours. The product was filtered off, washed withCH₃CN (3×), and dried at 50° C. in vacuo for 1 hour. Yield: 5.45 g ofintermediate 42 (94%).

e. Preparation of Intermediate 43

Ethyl 4-(1-piperazinyl)benzoic acid ester (3.732 g; 0.0159 mol) wasadded to a stirring mixture of intermediate 42 (4.9 g; 0.0159 mol) andCH₂Cl₂ (100 ml). TEA (4.478 ml; 0.0319 mol) was added, and the resultingsolution was stirred further at room temperature for 18 hours. Thereaction mixture was washed with NaHCO₃ aqueous saturated solution,dried with MgSO₄, filtered off, and evaporated. The residue was stirredin Et₂O, filtered off, washed with 3×Et₂O, and dried at 50° C. in vacuo.Yield: 6.55 g of intermediate 43 (81.35%; m.p. 161-167° C.).

f. Preparation of Intermediate 44

Intermediate 43 (5.88 g; 0.0116 mol) was added to 1,4-dioxane (75 ml)and stirred. NaOH (35 ml; 0.035 mol) was added gently and the reactionmixture was stirred for 18 hours at room temperature. A turbid mixturewas formed. The reaction mixture was stirred for another 72 hours atroom temperature. MeOH (25 ml) was added. The reaction mixture wasstirred for another 72 hours. HCl 1 N (35 ml) was added and the reactionmixture was stirred for 18 hours. Filtered off and washed with H₂O.Dried at 50° C. in vacuo for 24 hours. Yield: 4.88 g intermediate 44(88%).

Example A16

a. Preparation of Intermediate 46

DECP (3.168 g; 0.01942 mol) was added to a solution of2,6-dichlorobenzeneacetic acid (3.063 g; 0.01494 mol), ethyl4-(1-piperazinyl)benzoic acid ester (3.5 g; 0.01494 mol) and DIPEA (0.6ml) in THF (30 ml) at room temperature. The reaction mixture was stirredovernight at room temperature. Solid products were precipitated,filtered, washed with CH₃OH and dried in vacuo. Yield: 6 g ofintermediate 46 (95%).

b. Preparation of Intermediate 47

NaOH (3.418 g; 0.0854 mmol) was added to a suspension of intermediate 46(6 g; 0.0142 mol) in H₂O (30 ml), CH₃OH (30 ml) and dioxane (90 ml) atroom temperature. Then the reaction mixture was stirred at roomtemperature for 4 days. Then HCl 1N was added to the reaction mixture(pH≦3). The solid product was precipitated, filtered off, washed withH₂O and dried in vacuum. Yield: 5.2 g of intermediate 47 (93%).

Example A11

a. Preparation of Intermediate 48

DCM (75 ml) was added to 4-amino-3,5-dichlorobenzeneacetic acid (2.86 g;0.013 mol) and stirred, a turbid mixture was formed. After adding Et₃N(5.5 ml; 0.0391), pyrrolidine (1.3 ml; 0.0158 mol) was added. DECP (2.5ml; 0.015 mol) was added. A N₂-flow was added for a few minutes andvessel was closed. After 18 hours reaction mixture was extracted bywashing the DCM layer with a saturated aqueous NaHCO₃ solution andextracting the CH₂Cl₂-layer. This layer was dried with MgSO₄, filteredoff, evaporated and co-evaporated with toluene, yielding 4.317 g. Theresidue was purified by column chromatography over silica (eluent: 97/3CH₂Cl₂/MeOH). The pure fractions were collected and the solvent wasevaporated and co-evaporated with toluene. Yield: 3.104 g ofintermediate 48 (87%).

b. Preparation of Intermediate 49

Borane THF 1M (30 ml; 0.03 mol) was added to a mixture of intermediate48 (2.88 g; 0.0105 mol) in THF (dry) (60 ml) and was refluxed for 18hours. The reaction mixture was cooled to room temperature. The reactionmixture was added to a stirring solution of H₂O (300 ml) and HCl(concentrated) (300 ml) on an ice bath and refluxed for 30 minutes. Thereaction mixture was cooled again and put on an ice bath. K₂CO₃-powderwas added slowly. The reaction mixture was extracted with CH₂Cl₂ andsome water was added. The CH₂Cl₂-layer was separated, dried with MgSO₄,filtered off, evaporated and co-evaporated with toluene.

The residue was stirred in Et₂O and extracted with HCl 1N, layersseparated, extracted a second time with HCl 1N. HCl-layer was separatedand joint with the first fraction. It was neutralised with NaHCO₃ untilpH 8 and extracted with CH₂Cl₂. Some water was added to solve the saltsthat were precipitated. Layers were separated, CH₂Cl₂-layer was driedwith MgSO₄, filtered off, evaporated and co-evaporated with toluene.Dried in vacuo for 18 h at 50° C. The residue was stirred in Et₂O with1M HCl/Et₂O (15 ml), filtered off and washed with Et₂O. Yield: 3.05 g ofintermediate 49 (.HCl)(98%).

c. Preparation of Intermediate 50

Intermediate 49 (3 g; 0.0101 mol) was dissolved in HCl 1M in Et₂O (10ml; 0.01 mol) and CH₃CN dry (150 ml) at room temperature and stirred for30 minutes. 20% Phosgene in toluene (706 ml; 0.0152 mol) was added inportions to the stirring mixture. The reaction mixture was stirredsoftly for 20 hours at room temperature. Then, the reaction mixture wasevaporated and co-evaporated with toluene (dry). Yield: 2.89 g ofintermediate 50 (99%).

Example A18

a. Preparation of Intermediate 51

(3-Pyrrolidin-1-ylphenyl)methylamine (8 g; 0.0408 mol) was dissolved inDCM (50 ml). Et₃N (25 ml; 0.178 mol) was added to a stirring solution.1-(1,1-dimethylethyl)-4-(4-carboxyphenyl)-1-piperazinecarboxylic acidester (10.429 g; 0.034 mol) was added and the mixture was stirred.CH₂Cl₂ (100 ml) was added and then DECP (11.9 ml; 0.0796 mol) was added.The reaction mixture was stirred for 18 hours. Then the mixture wasstirred in a saturated NaHCO₃-solution. The organic layer was separated,dried with MgSO₄, filtered off, evaporated and co-evaporated withtoluene. Yield: 15.815 g of intermediate 51 (99%).

b. Preparation of Intermediate 52

Intermediate 51 (1 g; 0.00215 mol) was dissolved in iPrOH (125 ml) andHCl iPrOH (2.152 ml; 0.0129 mol) was added. The reaction mixture washeated to 60° C. and stirred for 18 hours. HCl iPrOH (0.36 ml; 1 eq) wasadded. The reaction mixture was stirred for 48 hours at 60° C. Thereaction mixture was evaporated and co-evaporated with toluene. Thereaction mixture was stirred in Et₂O and filtered off. The residue wasstirred for 1 hour in a NaHCO₃ solution and extracted with CH₂Cl₂.Layers were separated, CH₂Cl₂-layer was dried with MgSO₄, filtered off,evaporated and co-evaporated with toluene. The residue was stirred inDIPE and filtered off. Dried in vacuum at 50° C. for 18 hours. Yield:0.514 g of intermediate 52 (66%).

Example A19

a. Preparation of Intermediate 53

DECP (5.9 ml; 0.0395 mol) was added to a stirring solution of1-(1,1-dimethylethyl)-4-(4-carboxyphenyl)-1-piperazinecarboxylic acidester (10 g; 0.0326 mol) and 4-methoxybenzylamine (4.7 ml; 0.036 mol) inEt₃N (9.2 ml; 0.0655 mol) and CH₂Cl₂ (250 ml). The reaction mixture wasstirred at room temperature for 18 hours. Saturated NaHCO₃ solution (150ml) was added and the mixture was stirred for 30 minutes. Then H₂O (100ml) was added and the mixture was stirred for 30 minutes. The layerswere separated and CH₂Cl₂-layer was dried with MgSO₄, evaporated,co-evaporated with toluene and dried at 50° C. in vacuum for 3 hours.Yield: 15.21 g of intermediate 53 (107%).

b. Preparation of Intermediate 54

Intermediate 53 (0.998 g; 0.00235 mol) was added to CH₂Cl₂ (20 ml) andstirred, then TFA (1.75 ml; 0.0236 mol) was slowly added and the mixturewas stirred for 18 hours. CH₂Cl₂ and some excess of TFA were evaporatedand resolved in CH₂Cl₂ (100 ml). H₂O (200 ml) was added, the mixture wasstirred vigorous and some NaHCO₃ was added until there was no more CO₂produced and the water layer became basic. The layers were separated andthe CH₂Cl₂-layer was dried with MgSO₄, filtered off and evaporated(yield=0.682 g). The residue was stirred in DIPE and filtered off, driedat 50° C. in vacuo for 72 hours. Yield: 0.563 g of intermediate 54(74%).

Example A20

a. Preparation of Intermediate 55

DCM (25 ml) was added to 4-amino-3,5-dichlorobenzeneacetic acid (0.754g; 0.00343 mol) and stirred. Et₃N (1.45 ml, 0.0103 mol) was added, thenmethylpiperazine (0.46 ml; 0.00415 mol) was added. After adding DECP(0.65 ml; 0.00391 mol), some N₂ was flushed in and the vessel wasclosed. After 72 hours of stirring at room temperature the reactionmixture was stirred in a saturated solution of NaHCO₃ in water and thelayers were separated. The organic layer was dried with MgSO₄, filteredoff, evaporated and co-evaporated with toluene. Yield: 1.172 g. The drycompound was stirred in DCM with a saturated K₂CO₃-solution. The layerswere separated, some water was added. CH₂Cl₂-layer was dried with MgSO₄,filtered off, evaporated and co-evaporated with xylene. To purify theproduct from DECP, the HCl-salt was reacted by stirring the residue inHCl/2-propanol 6N (3 ml). The residue was dissolved in DIPE. After 15hours of stirring, the residue (solid) was filtered off and washed withDIPE. It was dried in vacuum for 1 hour at 50° C. Yield: 1.3 g ofintermediate 55 (99%).

b. Preparation of Intermediate 56

Intermediate 55 (1.3 g; 0.00384 mol) was dissolved in HCl 1M in Et₂O(4.2 ml; 0.0042 mol) and CH₃CN, dry (20 ml) at 0° C., 20% phosgene intoluene was added carefully to the stirring solution. The reactionmixture was stirred for 2 hours, then was removed from ice and wasstirred further at room temperature for 50 hours. 20% Phosgene intoluene (1.92 ml; 1 eq.) was added and the reaction mixture was stirredfurther for 36 hours. Then 20% Phosgene in toluene (1.0 ml; 0.5 eq.) wasadded. The reaction mixture was stirred for another 18 hours. Thereaction mixture was evaporated and co-evaporated with dry toluene.Yield: 1 g of intermediate 56 (79%). Residue was directly used in nextreaction step.

Example A21

a. Preparation of Intermediate 57

1,1-Dichloroethene (26.0 ml; 0.327 mol) was added dropwise to a mixtureof 1,1-dimethylethyl nitrous acid ester (20.0 ml; 0.167 mol) andanhydrous CuCl₂ (17.6 g; 0.131 mol) in 100 ml of anhydrous acetonitrilewell-cooled on ice bath. The reaction temperature was kept below 10° C.Then, 2,6-dichloro-4-methylbenzeneamine (19.2 g; 0.109 mol) dissolved inanhydrous acetonitrile (100 ml) was added dropwise at a temperaturebelow 15° C. The resulting mixture was stirred at room temperature untilthe evolution of gas has ceased, and the mixture was left overnight atroom temperature. The reaction mixture was poured carefully into 20% HCl(200 ml) and extracted with CH₂Cl₂ (3×100 ml). The combined organicphases were washed with 20% HCl, dried over Na₂SO₄ and concentrated invacuum. The resulting oil was diluted with hexane (100 ml) and filteredoff, yielding the crystalline product of2-(2,6-dichloro-4-methyl-phenyl)-acetamide. The filtrate wasconcentrated in vacuum at temperature below 50° C. Yield: 29.36 g ofintermediate 57 (crude product was used in the next step withoutadditional purification).

b. Preparation of Intermediate 58

Sodium metal (11.5 g; 0.502 mol) dissolved in MeOH (100 ml) was addeddrop-wise to a solution of intermediate 57 (29.361 g; 0.10 mol) in MeOH(100 ml). The mixture was refluxed for 5 hours. Sulfuric acid (95%, 20ml) was added to the cooled reaction mixture. The mixture was refluxedfor 1 hour, cooled to room temperature and poured into H₂O (500 ml). Themixture was extracted with CH₂Cl₂ (3×100 ml). The organic layers werecombined, dried over sodium sulphate and evaporated in vacuum. Theobtained product (28.088 g) was distilled in vacuum.

Yield: fraction 1: 2.999 g, fraction 2: 1.951 g and fraction 3: 13.127g.

Fraction 2 and Fraction 3 were combined and distilled one more time:

Yield: fraction 4: 2.649 g and 11.610 g of intermediate 58 (fraction 5).

c. Preparation of Intermediate 59

Methyl 2,6-dichloro-4-methylbenzene acetic acid ester (10.27 g; 0.044mol) was dissolved in CCl₄ (100 ml). Then NBS (9.41 g; 0.053 mol) andAIBN (0.363 g; 0.0022 mol) were added to the solution. The resultingmixture was refluxed at stirring for 10 hours. The solution was cooledand passed through a silica gel layer. Silica gel was washed with CCl₄(100 ml) and hexane (200 ml). The combined filtrates were concentratedin vacuum. The obtained residue became crystalline after cooling. Yield:12.85 g. The residue was recrystallized from hexane. Yield: 10.30 g ofintermediate 59 (mixture, used as such in the next step).

d. Preparation of Intermediate 60

Intermediate 59 (8.682 g) and pyrrolidine (6.86 ml; 0.0835 mol) weremixed and heated to 90-100° C. for 5 minutes. Water (50 ml) was added,and the resulting mixture was extracted with CH₂Cl₂ (3×50 ml). Thecombined organic layer was separated, dried over Na₂SO₄ and evaporatedin vacuo. The obtained residue (8.178 g as brown oil) was treated withether solution of HCl (2 M, 25 ml). A semi-crystalline precipitate wasobtained. An excess of HCl ether solution was decanted, ether (30 ml)was added to the precipitate and acetone was added drop-wise at stirringtill a crystalline product was formed. The formed precipitate wasfiltered off, washed with acetone and dried on the air. Yield: 5.347 gof intermediate 60 (43%).

e. Preparation of Intermediate 61

Intermediate 60 (5.00 g; 14.76 mmol) and LiOH.H₂O (1.24 ml; 29.53 mmol)were dissolved in a mixture of water (20 ml) and CH₃OH (40 ml) andrefluxed for 20 minutes. HCl concentrated (3 ml) was added and themixture was evaporated in vacuo. HCl concentrated (5 ml) was added andthe resulting suspension was diluted with acetone (20 ml). Thesuspension was refluxed for 5 minutes and cooled till room temperature.The formed yellowish crystalline product was filtered off, washed withacetone and dried on the air. Yield: 3.791 g of intermediate 61 (79%).

f. Preparation of Intermediate 62

TEA (1.20 ml; 8.62 mmol) was added to a suspension of intermediate 61(0.700 g; 2.156 mmol) in CH₂Cl₂ (15 ml). A clear solution formedimmediately. DECP (0.400 ml; 2.587 mmol) was added to the reactionmixture. The resulting mixture was stirred for 10 minutes at roomtemperature. A solution of 1-(4-nitrophenyl)piperazine (0.536 g; 2.587mmol) in CH₂Cl₂ (10 ml) was added to the reaction mixture. The mixturewas stirred for 5 hours at room temperature. The reaction mixture waswashed with 2% potassium carbonate aqueous solution, dried over Na₂SO₄and passed through silica gel pad. The obtained solution wasconcentrated in vacuum. The obtained residue was treated with hexane. Aformed crystalline product was filtered off and dried on the air. Yield:0.525 g of intermediate 62 (51%).

g. Preparation of Intermediate 63

Intermediate 62 (0.500 g; 1.047 mmol), hydrazine monohydrate (0.265 g;5.237 mmol) and Raney Nickel ®, 50% slurry in H₂O (0.50 g) dissolved inCH₃OH (50 ml) were stirred for 10 minutes at reflux. The catalyst wasfiltered from the hot solution and washed with hot methanol. Thefiltrate was concentrated in vacuum. The residue was treated with amixture of water and i-PrOH (1/1). A formed crystalline product wasfiltered, washed with small amount of i-PrOH, hexane and dried on theair.

The yield was 0.272 g of intermediate 63 (58%):

All filtrates after isolation of target compound were collected, dilutedwith water (20 ml) and extracted with CH₂Cl₂. CH₂Cl₂ solution was driedover Na₂SO₄ and concentrated in vacuum. The residue yielded 0.150 g ofintermediate 63 which was used on the next step without purification.

Intermediate 85

was prepared in a similar way.

Example A22

a. Preparation of Intermediate 64

2,6-Dichloro-4-chloromethylphenylamine (3.68 g; 0.0149 mol) was addedportionwise to a stirring solution (in a water bath) of1-methylsulfonylpiperazine (2.971 g; 0.0181 mol) and diisopropylamine(8.2 ml; 0.058 mol) in CH₃CN (100 ml). The reaction mixture was stirredfurther at room temperature for 18 hours. Two fractions P1 and P2 werepurified by reversed phase high-performance liquid chromatography(Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D.5 cm). A gradient with 3 mobile phases was applied. Phase A: 90% of a0.5% NH₄OAc solution in water+10% CH₃CN; phase B: CH₃OH; phase C:CH₃CN). The desired fraction was collected and worked-up. The solventwas evaporated and coevaporated with toluene. Yield: 2.24 g ofintermediate 64 (44%).

b. Preparation of Intermediate 65

HCl 1 M in Et20 (1.22 ml; 0.00244 mol) was added to a stirring solutionof intermediate 62 (750 mg; 0.00222 mol) in CH₃CN p.a. dried onmolecular sieves (10 ml). Stirring was continued for 15 minutes. Aprecipitate was formed. The reaction mixture was cooled on an ice-bath,and phosgene 20% in toluene (1.66 ml; 0.00332 mol) was added. Thereaction mixture was stirred further for 18 hours. The mixture wasfiltered, washed 3× with dry CH₃CN and dried for 18 hours in vacuo at50° C. Yield: 0.365 g of intermediate 65 (45%).

Example A23

a. Preparation of Intermediate 66

NaH 60% (0.396 g; 0.0099 mol) was added portionwise to a stirringsolution of 2,6-dichlorophenol (1.614 g; 0.0099 mol) in THF p.a. driedon molecular sieves (50 ml) under N₂ atm. After addition, stirring wascontinued for 15 minutes. 4-(4-nitrophenyl)-1-piperazinecarbonylchloride (0.89 g; 0.0033 mol) was added, and the reaction mixture wasstirred further at room temperature for 1 hour. The reaction mixture wasstirred further at reflux for 17 hours 30 minutes. The reaction mixturewas allowed to reach room temperature, and was poured into 200 mlice-water. Stirring was continued for 15 minutes. The product wasfiltered off, washed with 3× H₂0, and dried at 50° C. in vacuo. Yield:1.3 g of intermediate 66 (99%).

b. Preparation of Intermediate 67

A solution of intermediate 66 (1.3 g; 0.00328 mol) in acetic acid (50ml) and thiophene (6.901 ml; 0.00328 mol) was hydrogenated over Pt/C 5%(0.3 g). After the calculated amount of H₂ (0.00984 mol) was taken up,the catalyst was filtered off. The filtrate was evaporated, and 2×co-evaporated with toluene. The residue was dissolved in CH₂Cl₂, andwashed with NaHCO₃ aqueous saturated solution. The separated organiclayer was dried with MgSO₄, filtered off, and evaporated, andco-evaporated with toluene. The residue was stirred in Et₂O, filteredoff, washed with 3× Et₂O, and dried at 50° C. in vacuo. Yield: 0.94 g ofintermediate 67 (78%).

Example A24

a. Preparation of Intermediate 83

A solution of 4-methoxybenzeneacetic acid (5.0 g; 0.03009 mol) in CH₂Cl₂(100 ml) was stirred at room temperature.4-(4-Aminophenyl)-1-piperazinecarboxylic acid 1,1-dimethylethyl ester(8.35 g; 0.03009 mol) and Et₃N (6.3 ml; 0.04514 mol) were added. Then,EDCI (5.77 g; 0.03009 mol) and HOBT (4.07 g; 0.03009 mol) were added tothe mixture. The resultant reaction mixture was stirred overnight atroom temperature. The solvent was evaporated in vacuo. The residue waswashed with methanol, then dried. Yield: 11.9 g of intermediate 83(93%).

b. Preparation of Intermediate 84

A mixture of intermediate 83 (11.9 g; 0.028 mol) in 1,4-dioxane (20 ml)was stirred at room temperature. HCl, 4 M in 1,4-dioxane (50 ml; 0.200mol) was added to the mixture. Then the reaction mixture was stirred for2 hours at room temperature. The solvent was evaporated in vacuo. Yield10.0 g of intermediate 84 (99%).

Example A25

a. Preparation of Intermediate 68

4-Amino-3,5-dichlorobenzeneacetonitrile (3.41 g; 0.017 mol) wasdissolved in THF (25 ml) and borane in THF 1 M (25 ml; 0.025 mol) wasadded. After 72 hours the reaction mixture became turbid, yellow and agel. The reaction mixture was added to a stirring solution of 200 ml HCl1 M (in water) in ice, neutralised with NaHCO₃ (powder) and extractedwith CH₂Cl₂. The layers were separated, CH₂Cl₂-layer was dried withMgSO₄, filtered off, evaporated and co-evaporated with toluene.Yield=2.90 g. Water-layer was extracted again with CH₂Cl₂, separated,dried with MgSO₄, filtered off and evaporated. The water-layer wasextracted again like before. Different batches were combined yielding3.93 g. The product was purified by reversed-phase high-performanceliquid chromatography (Shandon Hyperprep® C18 BDS (Base DeactivatedSilica) 8 μm, 250 g, I.D. 5 cm). A gradient with 3 mobile phases wasapplied. Phase A: a 0.25% NH₄HCO₃ solution in water; phase B: CH₃OH;phase C: CH₃CN). The desired fractions were collected and worked-up. Thedesired fractions were evaporated, 3 x co-evaporated with methanol andco-evaporated with toluene. Dried for 18 hours in vacuo at 50° C.Yield=1.065 g of intermediate 68 (31%).

b. Preparation of Intermediate 69

Methyl p-tosylate (2.128 g; 0.0114 mol) solved in CH₂Cl₂ (70 ml) wasadded dropwise to a stirring solution of intermediate 68 (1.065 g;0.00519 mol) in DIPEA (2.146 ml; 0.013 mol) and CH₂Cl₂ (70 ml) at 0° C.The reaction mixture was kept at 0° C. for 8 hours then the mixture wasallowed to warm up to room temperature. After 152 hours the reactionmixture was filtered off and washed 1× with CH₂Cl₂. Dried in vacuo for18 hours at 50° C. Yield=1.230 g of intermediate 69 (56%).

c. Preparation of Intermediate 70

Phosgene 20% in toluene (895 μl; 1.5 eq.) was added to a stirringsolution of intermediate 69 (0.5 g; 0.00119 mol) in CH₃CN p.a. dried onmolecular sieves (10 ml) on an ice-bath. Phosgene 20% in toluene (600ml; 1 eq.) was added and the reaction mixture was stirred further atroom temperature. The reaction mixture was evaporated until no phosgene,the reaction mixture was concentrated. The crude reaction mixture wasused in the next reaction step.

Example A26

a. Preparation of Intermediate 71

3,4-Dihydro-2H-pyran (4.27 ml; 0.0468 mol) and 4-methyl-benzenesulfonicacid (0.02 g; 0.000116 mol) were added to a solution of2-fluoro-5-nitrobenzenemethanol (8.0 g; 0.0468 mol) in CH₂Cl₂ (200 ml)and stirred for 1 hour. The reaction mixture was washed with a saturatedaqueous NaHCO₃ solution (20 ml), H₂O (50 ml) and brine (20 ml). The twolayers were separated. The organic layer was dried (Na₂SO₄), filteredand the solvent was evaporated. Yield: intermediate 71 (crude used assuch in next reaction step).

b. Preparation of Intermediate 72

A mixture of intermediate 71 (0.0468 mol), 1-(phenylmethyl)piperazine(8.2 g; 0.0468 mol) and Na₂CO₃ (11.8 g; 0.0936 mol) in DMF (100 ml) waswarmed to 60° C. and stirred overnight. The solvent was evaporated andthe residue was partitioned between EtOAc (20 ml) and H₂O (400 ml). Thetwo layers were separated. The organic layer was dried with Na₂SO₄,filtered and the solvent was evaporated. The residue was purified oversilica gel on a glass filter (eluent: n-hexane/EtOAc from 100/0 to 5/2).The pure fractions were collected and the solvent was evaporated. Yield:13.2 g of intermediate 72 (68%).

c. Preparation of Intermediate 73

A mixture of intermediate 72 (13.0 g; 0.032 mol) in THF (150 ml) washydrogenated with Pt/C 5% (2 g) as a catalyst in the presence ofthiophene solution (1 ml). After uptake of H₂ (3 equiv), the catalystwas filtered off and the filtrate was evaporated. The reaction mixturewas concentrated to dryness. Yield: 12 g of intermediate 73 (98%).

d. Preparation of Intermediate 74

Benzenebutanoic acid (0.24 g; 0.0014 mol) in DMF (12 ml) was stirred atroom temperature. PS-Carbodiimide resin (1.4 g; 0.0026 mol) and thenHOBT (0.270 g; 0.002 mol) were added and the reaction mixture wasstirred for 30 minutes at room temperature. Intermediate 73 (0.5 g;0.0013 mol) in DMF (18 ml) was added and the reaction mixture was shakenovernight. MP-carbonate resin (1.4 g; 0.004 mol) and thenresin-linked-N═C═O (0.7 g; 0.0013 mol) were added to the reactionmixture. The reaction mixture was shaken overnight. The reaction mixturewas filtered and the filtrate's solvent was evaporated. Yield: 0.7 g ofintermediate 74.

e. Preparation of Intermediate 75

A mixture of intermediate 74 (0.7 g; 0.0013 mol) in THF (50 ml) washydrogenated at 50° C. with Pd/C 10% (0.2 g; 0.2 g) as a catalyst in thepresence of Et₃N (1 ml). After uptake of H₂ (1 equiv), the catalyst wasfiltered off and the filtrate was evaporated. Yield: intermediate 75(used as such in next reaction step)

f. Preparation of Intermediate 76

A mixture of intermediate 75 (0.7 g; 0.0016 mol) and1,3-dichloro-2-isocyanatobenzene (0.34 g; 0.0018 mol) in CH₂Cl₂ (10 ml)was stirred at room temperature for 2 hours. The solvent was evaporated.Yield: intermediate 76 (used as such in next reaction step)

Example A27

a. Preparation of Intermediate 77

EDCI (0.713 g; 3.72 mmol) was added to a solution ofγ-oxo-benzenebutanoic acid (0.602 g; 3.38 mmol), intermediate 9(prepared according to A4.b), HOBT (0.041 g; 0.3 mmol), DIPEA (0.67 ml;4.06 mmol) in THF/DMF 1:1 dried on molecular sieves (20 ml) and stirredat room temperature over the weekend. The reaction was evaporated todryness yielding 4.897 g. This residue was extracted with 1% citric acidand CH₂Cl₂, and the combined extract was washed with NaHCO₃ solution.The organic phase yielded 1.798 g. It contains 86% product and 14%starting material. While dissolving this residue in CH₃CN/MeOH (1/1 v/v)and acidifying it with a few drops of 12 N HCl followed by addition ofwater to ratio 1/4 water/organic solvents, for RP HPLC purification,some crystalline material was obtained, which was isolated and dried toyield 830 mg. In the filtrate a second crop crystalline material wasrecovered the same way yielding 233 mg, which is also pure compound.These two fractions were combined and purified by reversed phasehigh-performance liquid chromatography (Shandon Hyperprep® C18 BDS (BaseDeactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with 3 mobilephases was applied. Phase A: 90% of a 0.5% NH₄OAc solution in water+10%CH₃CN; phase B: CH₃OH; phase C: CH₃CN). The desired fractions werecollected and worked-up.

After partial evaporation of the solvent (to which a little Na₂CO₃solution was added to obtain an alkaline pH before the start of theevaporation), the solution was extracted with CH₂CL2, dried (MgSO₄) andworked up yielding 167 mg of intermediate 77.

b. Preparation of Intermediate 78

A mixture of intermediate 77 (1.052 g; 2.23 mmol) in CH₃OH (50 ml) washydrogenated at room temperature overnight with 10% Pd/C (0.3 g) as acatalyst. After work up the yield was 685 mg of intermediate 78 (91%).

Example A28

Preparation of Intermediate 79

HBTU (6.37 g, 16.80 mmol) is added to a solution of intermediate 38(prepared according to A4.d-1),2-chloro-α-[[(1,1-dimethylethoxy)carbonyl]amino]-benzeneacetic acid(4.00 g; 14. mmol), DIPEA (9.3 ml; 56 mmol) in DMF dried on molecularsieves (100 ml). The reaction mixture was stirred at room temperatureovernight. The reaction was evaporated to yield 22.53 g. The product waspurified by reversed-phase high-performance liquid chromatography(Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D.5 cm). A gradient with 2 phases was applied. Phase A: a 0.25% NH₄HCO₃solution in water; phase B: CH₃CN). The desired fractions were collectedand worked-up. After partial evaporation at 30-35° C., extraction withCH₂Cl₂ (2×400 ml) followed by EtOAc extraction (300 ml), drying (MgSO₄)and work up of the organic phases, 4512 mg residue was obtained fromCH₂Cl₂ and 45 mg from EtOAc. Yield: 4512 mg (54.3%) (mixture of R andS-enantiomers). This fraction was separated on SFC (column OJ-H, 30%CH₃OH containing 0.2% isopropylamine) into its enantiomers. Fraction Ayielded 1780 mg (R* enantiomer) and fraction B yielded 1770 mg ofintermediate 79 (S* enantiomer).

Example A29

a. Preparation of Intermediate 80

Pyrrolidine (45.2 g; 0.650 mol) was added dropwise to a solution of1-bromo-4-(bromomethyl)-2-chlorobenzene (168 g; 0.590 mol) and Et₃N (98ml; 0.708 mol) in THF (q.s.) (500 ml). The reaction mixture was stirredovernight. The mixture was washed with water, separated, dried overNa₂SO₄, filtered and evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂). The desired fractionswere collected and the solvent was removed. Yield: 50 g of intermediate80 (31%).

b. Preparation of Intermediate 81

Reaction under N₂ atmosphere. A solution of intermediate 80 (14.0 g;0.05099 mol) in THF (200 ml) was stirred at −78° C. for 15 minutes.n-BuLi, 2.5 M in THF (20 ml; 0.05099 mol) was added to the mixture overa period of 15 minutes. 30 minutes later, a solution of DMF (3.95 ml;0.05099 mol) in THF (20 ml) was added dropwise to the mixture. Thereaction temperature was allowed to rise to room temperature slowly, andthe mixture was stirred overnight. The reaction was quenched by addingwater at 0° C. The mixture was extracted with ethyl acetate (3×100 ml).The organic layers were combined, washed with brine, dried (MgSO₄),filtered and the solvent was evaporated in vacuo. Yield: 10.4 g ofintermediate 81. The crude product was used in the next step directlywithout further purification.

c. Preparation of Intermediate 82

To a solution of intermediate 81 (6 g; 0.0268 mol) in CH₂Cl₂ (50 ml) wasadded trimethylsilanecarbonitrile (6 ml) and ZnBr₂ (0.3 g). The reactionmixture was stirred for 5 hours at room temperature. Then the mixturewas heated to 50° C. and stirred overnight. The reaction mixture wascooled to 0° C. and HCl concentrated (q.s.) was added. The mixture wasstirred overnight at room temperature, then stirred and refluxed for 1hour. After cooling, the reaction mixture was poured into water andextracted with ethyl acetate. The solvent was evaporated to give 3.0 gcrude product. 0.8 g crude product was purified by preparative HPLC.(Ymc: 250×20 mm Mobile Phase: 0-25% CH₃CN % in H₂O (0.1%Trifluoro-aceticacid) Flow Rate: 15 ml/min Finished Time: 17.2 min). The productfractions were collected and the solvent was evaporated. Yield: 0.1 g ofintermediate 82.

B. Preparation of the Final Compounds

Example B1

Preparation of Compound 1

Cyclohexane acetic acid (0.00012 mol) was dissolved in DMF (1.2 ml).PS-Carbodiimide, 2.1 mmol/g) and HOBT (0.00015 mol) were added. Thereaction mixture was shaken for 30 minutes. A solution of intermediate 5(prepared according to A2.b) (0.0001 mol) in DMF (2 ml) was added. Thereaction mixture was shaken overnight. MP-carbonate, 6.2 mmol/g (0.00045mol) and resin-linked-NCO, 1.8 mmol/g (0.0001 mol) were added. Themixture was shaken overnight at room temperature. The mixture wasfiltered. CH₂Cl₂ (2 ml) was added. The mixture was shaken for one hour,then filtered again. The filtrate's solvent was evaporated (GeneVac).The residue was purified by HPLC. The product fractions were collectedand worked-up. Yield: 0.0128 g of compound 1.

Example B2

a. Preparation of Compound 2

EDCI (0.000302 mol) was added to a mixture of intermediate 5 (preparedaccording to A2.b) (0.000275 mol),1-(acetylamino)-cyclopentanecarboxylic acid (0.000275 mol), HOBT(0.000028 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.000329mol) in THF, dried over 3 Å molecular sieves (5 ml) and then stirred for64 hours at room temperature. The solvent was evaporated. The residuewas dissolved in CH₃OH (5 ml). The solution's solvent was evaporated(under N₂). The dried residue was purified by reversed-phasehigh-performance liquid chromatography. (Shandon Hyperprep® C18 BDS(Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with thementioned mobile phases was applied (phase A: a 0.25% NH₄HCO₃ solutionin water; phase B: CH₃OH (optional); phase C: CH₃CN). The desiredproduct fraction was collected and the solvent was evaporated and thenco-evaporated with CH₃OH. Yield: 0.038 g of compound 2.

b. Preparation of Compound 3

EDCI (0.0015 mol) was added to a solution of intermediate 5 (preparedaccording to A2.b) (0.0014 mol), 3-phenoxypropanoic acid (0.0014 mol),HOBT (0.0001 mol) and THF/DMF 1/1 dry (10 ml) inN-ethyl-N-(1-methylethyl)-2-propanamine (0.272 ml) and then stirred for116 hours at room temperature. The solvent was evaporated. The residuewas purified by reversed-phase high-performance liquid chromatography(Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D.5 cm). A gradient with the mentioned mobile phases was applied (phase A:(0.5% NH₄OAc in H₂O)/CH₃CN 90/10); phase B: CH₃OH (optional); phase C:CH₃CN). The product fractions were collected and the solvent wasworked-up. Yield: 0.293 g of compound 3.

c. Preparation of Compound 4

A mixture of N-(2-chlorophenyl)glycine (0.377 mmol), EDCI (0.377 mmol)and Et₃N in CH₂Cl₂ (6 ml) was stirred for 20 minutes at roomtemperature. Then intermediate 5 (prepared according to A2.b) (0.342mmol) and HOBT (0.377 mmol) were added and the stirring was continuedfor 24 hours at room temperature (control by LC/MS). The solvent wasremoved under reduced pressure. The residue was treated with water; theformed precipitate was filtered off and washed with water. The targetproduct was purified by flash-chromatography (eluent: CH₂Cl₂/MeOH—50/1)and then by HPLC (CH₃CN/H₂O—9/1). The desired fractions were collectedand worked-up. Yield: 0.021 g (11.5%) of compound 4 (beige crystallinepowder).

d. Preparation of Compound 5

A mixture of intermediate 5 (prepared according to A2.b) (2.73 mmol),1-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopentanecarboxylic acid (2.75mmol) and HOBT (2.8 mmol) in Et₃N (0.4 ml) and DMF, p.a., dried onmolecular sieves (50 ml) was stirred at room temperature. EDCI (2.8mmol) was added. The reaction mixture was stirred under N₂ atmospherefor 18 hours at room temperature. The solvent was evaporated. Theresidue was stirred in water (50 ml), filtered off, washed with water,then dried at 50° C. (vacuum, stream of air). The product was stirred inboiling ethanol (60 ml), filtered hot through dicalite and the filtratewas stood for 3 days. The product was filtered off, washed with ethanol(3×), and dried at 50° C. under vacuum. Yield: 0.44 g of compound 5(28%).

e. Preparation of Compound 6

DMF (0.2 ml) was added to a mixture of intermediate 34 (preparedaccording to A13.b) (1.50 mmol) and ethanedioyl dichloride (2.00 mmol)in DCM (7 ml). Then the reaction mixture was stirred at room temperaturefor 2 hours. The solvent was removed under reduced pressure. The residuewas resuspended in CHCl₃ (10 ml), then the solvent was evaporated again.The residue dissolved in DCM (2 ml) was added to a mixture ofintermediate 5 (prepared according to A2.b) and Et₃N (0.280 ml) in C₆H₆(8 ml). The reaction mixture was refluxed for 4 hours and held overnightat room temperature. Then the solvent was removed under reduced pressureand the residue was washed with water. Precipitate was filtered off,washed with water and with the mixture of ether-ethanol. Yield: 0.380 gof compound 6 (51%).

f. Preparation of Compound 7

A mixture of intermediate 32 (prepared according to Al2.b) (1.200 mmol),TBTU (1.400 mmol) and Et₃N (0.031 ml) in CH₃CN (10 ml) was stirred atroom temperature for 1 hour. Then intermediate 5 (prepared according toA2.b) was added and stirring was continued at room temperature for 18hours. The formed precipitate was filtered off, washed with ether anddried on air. Yield: 0.479 g of compound 7 (82%).

Example B3

Preparation of Compound 8

Heptanoyl chloride (0.0014 mol) was added to a solution of intermediate5 (prepared according to A2.b) (0.0014 mol) andN-ethyl-N-(1-methylethyl)-2-propanamine (0.210 ml) in CH₂Cl₂ (20 ml) andDMF, dry (0.1 ml) and was then stirred at room temperature for 17 hours.The solvent was evaporated. The residue was stirred in H₂O (10 ml) andCH₃OH (1 ml). Na₂CO₃ (0.2 g) was added to the mixture and stirred for 1hour. The precipitate was filtered off, washed with EtOAc and washedwith Et₂O. The residue and the filtrate were combined again. The organicsolvents were evaporated to leave an aqueous concentrate. This mixturewas stirred and the resulting precipitate was filtered and washed withEt₂O. The residue is dried (vacuo). Yield: 0.395 g of compound 8.

Example B4

a. Preparation of Compound 9

Intermediate 5 (prepared according to A2.b) (0.410 mmol),2-pyridinepropanoyl chloride hydrochloride (prepared according toart-known procedures) (0.435 mmol) and Et₃N (0.133 ml) were dissolved inCH₃CN (5 ml) and stirred for 5 hours at 80° C. Then, 5 ml water wasadded, and the reaction mixture was extracted with DCM. The extract wasdried over Na₂SO₄ and concentrated in vacuum. The resulting residue waspurified by column chromatography on silica gel (eluent:DCM/methanol—10/1). Yield: 0.014 g of compound 9 (7%).

b. Preparation of Compound 351

4-Methoxybenzeneacetyl chloride (0.135 g; 0.730 mmol) was added to asolution of intermediate 63 (prepared according to A21.g) (0.272 g;0.608 mmol) and TEA (0.130 ml; 0.912 mmol) dissolved in DCM (5 ml). Thereaction mixture was stirred for 0.5 hours at room temperature. Thereaction mixture was concentrated in vacuum. The residue was treatedwith i-PrOH /hexane (3/1). A formed crystalline product was filtered,washed with small amount of i-PrOH, hexane and dried on air. Yield:0.098 g of compound 351 (45%).

Example B5

Preparation of Compound 10

NaH 60% (0.000183 mol) was added to a mixture of intermediate 28(prepared according to A9.b) (0.000166 mol) in DMF (2 ml; dried over 3 Åmolecular sieves) and stirred for 155 minutes. This mixture was added toheptanoylchloride (0.000332 mol) in THF (1 ml; dried over 3 Å molecularsieves) and then stirred for 24 hours at room temperature. The solventwas evaporated. The residue was purified by reversed-phasehigh-performance liquid chromatography. (Shandon Hyperprep® C18 BDS(Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with thementioned mobile phases was applied (phase A: a 0.25% NH₄HCO₃ solutionin water; phase B: CH₃OH (optional); phase C: CH₃CN). The productfractions were collected and worked-up. Yield: 0.043 g of compound 10(lightly brown oily gum)

Example B6

a. Preparation of Compound 11

A mixture of intermediate 11 (prepared according to A4.d) (0.0002 mol)and 1-bromo-2-isocyanato-3,5-dimethylbenzene (0.0002 mol) in DCM (3 ml)was stirred for 2 hours at room temperature. The solvent was evaporated.Yield: 0.060 g of compound 11.

b. Preparation of Compound 12

A mixture of intermediate 11 (prepared according to A4.d) (0.0005 mol),intermediate 30 (prepared according to A11) (0.0005 mol), and DCM (3ml), was stirred at room temperature for 48 hours. The solid part wasfiltered off, washed with 3×DCM, and dried at 50° C. (vacuum). Yield:0.24 g. This fraction was stirred in 5 ml DCM/MeOH 90/10 for 5 hours,and filtered off, and washed with 2×DCM/MeOH 90/10. The filtrate wasevaporated, stirred in 5 ml boiling EtOH, filtered off hot, washed with3×hot EtOH, and dried at 50° C. (vacuum). Yield: 0.03 g of compound 12(13%).

c. Preparation of Compound 13

Intermediate 11 (prepared according to A4.d) (0.0005 mol) was added to astirring solution of1,3-dichloro-2-isocyanato-5-(trifluoromethoxy)benzene (0.00125 mol) andDCM (3 ml). The reaction mixture was stirred further at room temperaturefor 18 hours. More 1,3-dichloro-2-isocyanato-5-(trifluoromethoxy)benzene(0.00125 mol) was added, and the reaction mixture was stirred further atroom temperature for 24 hours. The solvent was evaporated. The residuewas filtered over silica using DCM/MeOH 98/2 as eluent. The desiredfractions were combined and evaporated, and co-evaporated with MeOH.Yield: 0.051 g of compound 13 (17%).

d. Preparation of Compound 14

1,3-Dichloro-2-isocyanatobenzene (0.256 mmol) was added to a solution ofintermediate 18 (prepared according to A6.d) (0.270 mmol) inacetonitrile (5 ml). The reaction mixture was stirred at roomtemperature for 24 hours. The formed precipitate was filtered off,washed with DCM and dried on air. According to LC/MS, about 10% ofintermediate 18 remained in the reaction mixture. Therefore theprecipitate was diluted with DCM (5 ml) and1,3-dichloro-2-isocyanatobenzene (0.008 g) was added to this suspension.The mixture was stirred for 24 hours at room temperature. Formedprecipitate was filtered off, washed with DCM and dried on air. Yield:0.095 g of compound 14 (67%).

e. Preparation of Compound 223

A mixture of intermediate 38 (prepared according to A4.d-1) (0.97 g;0.0023 mol), Et₃N (2.8 ml; 0.0200 mol), CH₃CN, dried on molecular sieves(20 ml), and DMF, dried on molecular sieves (5 ml), was added to astirring mixture of intermediate 41 (prepared according to A15.c)(crude; 0.0023 mol) and CH₃CN, dried on molecular sieves (20 ml). Thereaction mixture was stirred further at room temperature for 2 hours.The reaction mixture was poured into 200 ml H₂O, and the product wasextracted with 150 ml CH₂Cl₂. The separated organic layer was washedwith NaHCO₃ aqueous saturated solution, dried with MgSO₄, filtered off,and evaporated. The residue was stirred in CH₃CN, filtered off, washedwith 3× CH₃CN, and dried at 50° C. (vacuum). Yield: 0.75 g of compound223 (54.7%).

Compound 223a (methanesulfonic acid salt)

Compound 223 was converted into its methanesulfonic acid salt (mesylatesalt) by adding methanol (70 ml; 1.73 mol) to compound 223 (4g; 6.71mmol) and then methanesulfonic acid (1 equiv.; 6.71 mmol) was added.After 30 minutes of stirring at room temperature, the solution wasevaporated to dryness. The solidified material was then triturated withacetone (60 ml), filtered off, washed with acetone and DIPE, dried invacuum oven at 45° C. for 3 hours, yielding 0.87 g of compound 223a(methanesulfonic acid salt).

3.3g of compound 223a prepared in this way (combination of differentbatches) was further suspended in PGMEE (polyethyleneglycolmonomethylether or 1-methoxy-2-propanol) at 90° C. After cooling down toroom temperature, the product crystallized after 2 days under stirring.The crystallized material was filtered off, washed with PGMEE (5 ml) anddried in a vacuum oven at 45° C., yielding 0.87 g of compound 223a.

f. Preparation of Compound 227

Intermediate 52 (prepared according to A18.b) (0.514 g; 1.41 mmol) wasdissolved in TEA (1 ml; 7.115 mmol) and DCM (50 ml) and intermediate 50(prepared according to A17.c)(0.402 g; 1.41 mmol) were added anddissolved in 100 ml DCM (50 ml; 2500 mmol). The reaction mixture wasstirred for 48 hours. The reaction mixture was stirred in saturatedsolution of NaHCO₃ in H₂O. To the layers was added CH₂Cl₂/MeOH 90/10 andwater. The layers were separated, the CH₂Cl₂-layer was dried with MgSO₄,filtered off, evaporated and co-evaporated. The residue was stirred inDIPE and filtered off, washed with EtOH and washed one time with DIPE.The filtrate precipitated and was filtered off, washed with DIPE anddried in vacuum at 50° C. for 18 hours. Yield: 0.369 g of compound 227(40%).

g. Preparation of Compound 228

Intermediate 56 (prepared according to A20.b) (0.5 g; 0.00152 mol) wasdissolved in DCM (10 ml) and was stirred. The solution was added to astirring solution of intermediate 54 (prepared according to A19.b) (0.5g; 0.00152 mol) in TEA (1 ml) and DCM (20 ml). The reaction mixture wasstirred in NaHCO₃ saturated aqueous solution. The layers were separated,the organic layer was dried with MgSO₄, filtered off, evaporated andco-evaporated with toluene, yielding 1.33 g.

The product was purified by reversed-phase high-performance liquidchromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8μm, 250 g, I.D. 5 cm). A gradient with 3 mobile phases was applied.Phase A: a 0.25% NH₄HCO₃ solution in water; phase B: CH₃OH; phase C:CH₃CN). The desired fractions were collected and evaporated until dry,co-evaporated with MeOH and afterwards with toluene. The residue wasstirred in Et₂O, filtered off, dried in vacuo for 18 hours at 50° C.Yield: 0.330 g of compound 228 (33%).

h. Preparation of Compound 268

Intermediate 65 (prepared according to A22.b) (0.365 g; 0.001 mol) wasadded to a stirring solution of intermediate 38 (prepared according toA4.d-1) (0.326 g; 0.001 mol) in triethylamine (0.704 ml; 0.00501 mol)and CH₂Cl₂ (10 ml). After 3 hours of continuous stirring, formation ofprecipitation was observed. The stirring was slowed down. After 36 hoursof slow stirring the reaction mixture was filtered off, washed 3× withCH₂Cl₂ and dried in vacuo at 50° C. for 20 hours. Yield: 0.335 g ofcompound 268 (48%).

i. Preparation of Compound 317

Intermediate 38 (prepared according to A4.d-1) (1.183 g; 0.00281 mol)was dissolved in DMF (5 ml) and extracted with CH₂Cl₂/NaHCO₃ saturatedsolution. The layers were separated and the CH₂Cl₂-layer was dried withMgSO₄ and filtered off. Intermediate 70 (prepared according to A25.c)(crude reaction mixture in CH₃CN) was added to the filtrate in CH₂Cl₂(25 ml) with DIPEA (0.557 ml; 0.00337 mol). After 18 hours, aprecipitate was formed, it was filtered off, washed 1× with CH₂Cl₂/DMFand 2× with CH₂Cl₂ and dried in vacuo for 20 hours at 50° C. Yield=0.573 g of compound 317 (80%).

Example B7

a. Preparation of Compound 15

Trichloromethyl carbonochloridic acid ester (0.0065 mol) was added tothe solution of 2,6-dichloro-4-methoxybenzenamine (0.001 mol) and Et₃N(0.4 ml) in dry toluene (16 ml). The reaction mixture was stirred for 2hours at 60° C. till the starting aniline reacted completely (control byTLC). Then, a solution of intermediate 24 (prepared according to A8.c)in DCM (4 ml) was added to the reaction mixture at 60° C. at stirring.Formation of precipitate was observed. The stirring was continued at60-70° C. for 1 hour. Then, the reaction mixture was concentrated invacuum. The formed sediment was treated with water and filtered off.Then, it was washed with water, ethyl acetate, ether, and dried on theair. Yield: 0.360 g of compound 15 (66%).

b. Preparation of Compound 16

Trichloromethyl carbonochloridic acid ester (0.001 mol) was added to asolution of 4-amino-3,5-dichlorophenol (0.002 mol) in dry ethyl acetate(30 ml) while cooling, and then the reaction mixture was refluxed for 2hours followed by addition of intermediate 24 (prepared according toA8.c) (0.00154 mol) in chloroform. The reaction mixture was refluxed for19 hours. The formed solid was filtered off and dried on the air. Theproduct was purified by washing the sediment with hot methanol. Theformed sediment was refluxed with methanol (10 ml) and then filtered offYield: 0.260 g of compound 16 (32%, white solid compound).

Example B8

Preparation of Compound 17

A mixture of intermediate 36 (prepared according to A14.b) (0.2 mmol)and N-ethyl-N-(1-methylethyl)-2-propanamine (q.s.) in DCM (2 ml) wasstirred at 10° C. A mixture of 2-methylbenzenesulfonylchloride (0.2mmol) in CH₂Cl₂ (1 ml) was added dropwise and the reaction mixture wasstirred at room temperature for 1 hour. The solvent was evaporated. Theresidue was purified by reversed phase high performance liquidchromatography. The product fractions were collected and worked-up. Theresidue was dissolved in DCM and dried over an Isolute filter. Thefiltrate was evaporated. Yield: 0.057 g of compound 17.

Example B9

Preparation of Compound 18

A mixture of intermediate 11 (prepared according to A4.d) (0.433 mmol)and 1-(2,6-dichlorophenyl)-3-(dimethylamino)-2-propen-1-one (0.476 mmol)in EtOH, p.a. (4 ml) was stirred in a sealed tube at 110° C. for 85hours. The reaction mixture was allowed to reach room temperature andthe solvent was evaporated. The residue was filtered purified silica gelusing DCM/MeOH (98:2) as eluent. The desired fractions were collectedand the solvent was evaporated and co-evaporated with EtOH. The residuesolidified upon standing. The product was stirred in EtOH (2.5 ml),filtered off, washed with EtOH, filtered off again and dried at 50° C.(vacuum). Yield: 0.127 g of compound 18 (56%).

Example B10

a) Preparation of Compound 19

EDCI (0.0012 mol) was added to a mixture of 2-chloro-α-hydroxybenzeneacetic acid (0.0011 mol), intermediate 11 (prepared according to A4.d)(0.0011 mol), HOBT (0.0001 mol) andN-ethyl-N-(1-methylethyl)-2-propanamine (0.213 ml) in DMF/THF (1/1 driedon molecular sieves) (10 ml) at room temperature. A second reactionmixture with 0.050 g of 2-chloro-α-hydroxybenzene acetic acid was set up(same conditions) and both mixtures were combined and evaporated todryness. The residue was purified by HPLC method A. The recoveredfraction was partially evaporated at 22° C. to remove the volatiles,followed by extraction with CH₂Cl₂. After drying (MgSO₄), filtration andevaporation 380 mg yellow oily residue was obtained. This was suspendedin boiling DIPE with few drops MeOH and stirred overnight at roomtemperature. After filtration and drying in vacuo at 50° C. a whitepowdery material was recuperated. Yield: 328 mg of compound 19 (RS).

b) Preparation of Intermediate 352

Intermediate 29 (prepared according to A29.c) (0.2 g; 0.00074 mol) inCH₂Cl₂ (10 ml) was stirred at room temperature. Et₃N (0.3 ml; 0.00222mol) was added, then EDCI (0.14 g; 0.00074 mol) and HOBT (0.1 g; 0.00074mol) were added. Intermediate 84 (prepared according to A24.b) (0.2 g;0.00074 mol) was added to the mixture. The resultant reaction mixturewas stirred overnight at room temperature. Water was added, and themixture was extracted with CH₂Cl₂ (3×10 ml), The organic layers werecombined, dried (MgSO₄), filtered and the solvent was evaporated invacuo. The residue was purified by high performance liquidchromatography (Column: Venusil 250×21.5 mm, Mobile Phase: 21-51% CH₃CN% (0.1% TFA), Flow Rate: 15 ml/min, Finished Time: 20 min). The desiredfraction was collected and evaporated to remove CH₃CN in vacuo. Theresidue was neutralized to pH=8 with saturated NaHCO₃, then extractedwith CH₂Cl₂ (3×10 ml). The organic layers were combined, washed withbrine, dried over MgSO₄, filtered and the filtrate's solvent wasevaporated in vacuo. Yield: 0.050 g of compound 352 (12%).

Example B11

a. Preparation of Compound 20

A mixture of intermediate 25 (prepared according to A1.d) (0.0001 mol),2-propen-1-amine (0.0001 mol) and Na₂CO₃ (0.0001 mol) in DMF (3 ml) wasstirred for 18 hours at room temperature. The solvent was evaporatedunder a stream of N₂ at 50° C. The residue was stirred in water (2 ml).This mixture was extracted with DCM (10 ml). The separated organic layerwas filtered through an Isolute filter (for drying). The filtrate'ssolvent was evaporated under a stream of N₂ at 50° C. Yield: 0.015 g ofcompound 20.

b. Preparation of Compound 21

A mixture of intermediate 26 (prepared according to A2.c) (0.000247mmol), benzenamine (0.000247 mol) and K₂CO₃ (0.000371 mol) was stirredin DMF (2 ml) at room temperature for 24 hours. Then the reactionmixture was heated up to 50° C. and the stirring was continued for 8hours at 50° C. (control by LC/MS). After that water (10 ml) was addedto the reaction mixture, the formed precipitate was filtered off andwashed with water. The residue was purified by column chromatography(eluent:ethyl acetate/acetone—1/1). Yield: 0.050 g of compound 21 (41%)(white crystals).

c. Preparation of Compound 22

A mixture of intermediate 26 (prepared according to A2.c) (0.000411mol), 2,4-dimethylbenzenamine (0.000432 mol) and Et₃N (0.070 ml) wasstirred in DMF (10 ml) at room temperature for 20 hours (control byLC/MS). When the reaction was completed the solvent was evaporated underreduced pressure. The residue was separated by column chromatography(eluent: DCM/MeOH—20/1). Yield: 0.042 g of compound 22 (21%) (whitecrystals).

Example B12

Preparation of Compound 23

A mixture of intermediate 3 (prepared according to A1.c) (max. 0.0002mol) and trifluoro acetic acid (0.2 ml) in CH₂Cl₂ (2 ml) was shaken for4 hours at room temperature. The solvent was evaporated. Toluene wasadded and azeotroped on the rotary evaporator. Yield: 0.068 g ofcompound 23 (S-enantiomer).

Example B13

Preparation of Compound 24

CH₃NH₂, 40% in H₂O (1 ml) was added to a stirring mixture ofintermediate 29 (prepared according to A10) (0.0003 mol) and CH₃CN (2.5ml) on an ice-bath. The resulting solution was stirred further at 0° C.for 5 minutes, and at room temperature for 18 hours. The solvents wereevaporated. The residue was purified by reversed-phase high-performanceliquid chromatography. (Shandon Hyperprep® C18 BDS (Base DeactivatedSilica) 8 μm, 250 g, I.D. 5 cm). A gradient with the mentioned mobilephases was applied (phase A: a 0.25% NH₄HCO₃ solution in water; phase B:CH₃OH (optional); phase C: CH₃CN). The desired fractions were combinedand the organic volatiles were evaporated. The product was filtered off,washed with 3×H₂O, and dried at 50° C. (vacuum). Yield: 0.05 g ofcompound 24 (33%).

Example B14

a. Preparation of Compound 25

Compound 222 (prepared according to B11.c) (0.000161 mol) was dissolvedin HCl (5 ml of 15% aqueous solution) and stirred for 4 hours at roomtemperature. The reaction mixture was held overnight. Insoluble sedimentwas filtered off through the folded filter. A saturated Na₂CO₃ solutionwas added to the filtrate up to pH=10. The formed precipitate wasfiltered off, washed with water and 3% aqueous solution of Na₂CO₃. Thenit was purified by column chromatography (eluent: ethylacetate/acetone—1/1). Yield: 0.024 g of compound 25 (30%)(whitecrystalline powder).

b. Preparation of Compound 26

Et₃N (0.093 ml) was added to a suspension of compound 25 (preparedaccording to B14.a) in CH₃CN (7 ml) and this mixture was stirred for 10minutes at 40° C. Then methanesulfonyl chloride (0.023 ml) was addeddropwise at stirring. The reaction mixture was refluxed for 2 hours atstirring (control by LC/MS). The solvent was removed under reducedpressure. The target product was purified by flash-chromatography(eluent: CH₂Cl₂/MeOH—10/1). Yield:0.055 g of compound 26 (36%) (whitecrystalline powder).

Example B15

Preparation of Compound 27

1N NaOH aqueous solution (0.4 ml) was added to a stirring mixture ofcompound 47 (prepared according to B6.a) (0.0001 mol) and 1,4-dioxane (2ml). The resulting solution was stirred further at room temperature for2 hours. The reaction mixture was cooled on an ice-bath, and 0.4 ml HCl1N was added. The volume was concentrated to about 0.5 ml, and 4 ml H₂Owas added. The mixture was stirred for 1 hour, filtered off, washed with3×H₂O, and dried at 50° C. (vacuum). Yield: 0.067 g of compound 27(91%).

Example B16

Preparation of Compound 28

2M LiBH₄ in THF (2 ml) was added to a stirring mixture of compound 47(prepared according to B6.a) (0.0005 mol) and THF p.a. (6 ml) (dried onmolecular sieves). The resulting solution was stirred further at roomtemperature for 18 hours. More 2M LiBH₄ in THF (0.8 ml) was added, andthe reaction mixture was stirred further at room temperature for 24hours. More 2M LiBH₄ in THF (0.4 ml) was added, and the reaction mixturewas stirred further at room temperature for 65 hours. To the reactionmixture was added slowly 20 ml H₂O, then 20 ml DCM. Stirring wascontinued for 5 hours. The solid part was filtered off, washed with2×H₂O, and 2×DCM, and dried at 50° C. (vacuum). Yield: 0.12 g ofcompound 28 (42%).

Example B17

Preparation of Compound 29

NaBH₄ (0.0072 mol) was added portionwise to a stirring mixture ofcompound 53 (prepared according to B6.a) (0.0060 mol) and CH₃OH (100ml). The reaction mixture was stirred further at room temperature for 18hours. The reaction mixture was cooled on a cold water batch, and 40 mlH₂O was added dropwise. After addition, stirring was continued for 1hour, then the mixture was left standing for 2 hours. The solid part wasfiltered off, washed with 3×15 ml MeOH/H₂O 1/2, and dried at 50° C.(vacuum, airstream). Yield: 2.85 g of compound 29 (86%).

Example B18

Preparation of Compound 30

The mixture of the compound 190 (prepared according to B7.a) (0.00117mol) and BBR₃ (0.0047 mol) in dry dichloroethane (15 ml) was stirred for10 hours at 20° C. and hold for a night at room temperature. Then, thereaction mixture was poured out on a cooled aqueous ammonia solution (50ml 7%-solution, 5° C.) while stirring. The mixture was filtered and thesediment was washed with water, with a mixture of ether/ethanol (4/1);ether, and dried on the air. Yield: 0.480 g of compound 30 (78%).

Example B19

Preparation of Compound 31

A mixture of compound 221 (prepared according to B2.f) (0.00216 mol),1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione (0.011 mol) and Pd(PPh₃)₄(0.00026 mol) in dry dichloroethane (40 ml) was stirred at 50° C. for 6hours under argon atmosphere. The solvent was removed in vacuum. Theresidue was dissolved in CH₂Cl₂ (50 ml). The resulting solution wasfiltered to remove insoluble components and washed with aqueous K₂CO₃(40 ml 10% solution). The organic layer was separated, washed withwater, dried over MgSO₄ and concentrated in vacuum. The dark-red residuewas purified by column chromatography on silica gel (eluent:CHCl₃/Me₂CO—7/1). The fractions containing a target product wereconcentrated. Yield: 0.78 g of compound 31 (white-pink powder).

Example B20

Preparation of Compound 32

A mixture of compound 173 (prepared according to B2.c) (0.000458 mol),2-mercapto acetic acid (0.064 ml) and LiOH.H₂O (0.000456 mol) in DMF (6ml) was stirred at room temperature for 24 hours. The reaction mixturewas diluted with water and the formed precipitate was filtered off,washed with water and dried on air. The residue was purified byflash-chromatography (eluent: DCM/MeOH 20/1). Yield: 0.040 g of compound32 (16%) (crystalline powder).

Example B21

a) Preparation of Compound 224

DECP (0.412 ml; 0.00276 mol) was added to a stirring mixture ofintermediate 44 (prepared according to A15.f) (0.94 g; 0.00197 mol),3-(1-pyrrolidinyl)-benzenemethanamine (0.482 g; 0.00246 mol), CH₂Cl₂p.a. (20 ml) and TEA (0.553 ml, 0.00394 mol). The reaction mixture wasstirred at room temperature for 24 hours. The solid part was filteredoff, washed with CH₂Cl₂ (3×), and dried at 50° C. in vacuo. Yield: 0.94g of compound 224 (75%; m.p. 224-230° C.)

b) Preparation of Compound 225

DECP (0.108 g; 0.00066 mol) was added to a solution of intermediate 47(prepared according to A16.b) (0.2 g; 0.000509 mol),3,5-dimethoxybenzenemethanamine (0.102 g; 0.00061 mol) and DIPEA (0.1ml) in CH₃CN (5 ml) at room temperature. Then the reaction mixture wasstirred at room temperature for 1 hour. Then the reaction mixture wasconcentrated to be dry, the residues were washed with EtOAc. Yield: 159mg of compound 225 (58%).

Example B22

Preparation of Compound 267

TEA (0.84 ml; 6.04 mmol) was added to a suspension of intermediate 61(prepared according to A21.e) in CH₂Cl₂ (15 ml). DECP (0.275 ml; 1.811mmol) was added to the reaction mixture. The mixture was stirred for 10minutes at room temperature. Intermediate 52 (prepared according toA18.b) (0.660 g; 1.811 mmol) was added to the reaction mixture. Themixture was stirred for 3 hours at room temperature. The crystallineproduct was filtered off, washed with CH₂Cl₂ and dried on the air.Yield: 0.313 g of compound 267 (27%).

Example B23

Preparation of Compounds 270 and 271

Compound 29 (prepared according to B17) (0.08 g, 0.0001 mol) wasseparated into its enantiomers by supercritical fluid chromatographyover an AS—H column (diameter: 20 mm×length: 250 mm); method: gradientelution with (20-60% 2-propanol with 0.2% 2-propylamine)/CO₂ (at 1.6rate and hold 0.1 min); flow: 40 ml/min; column heater: 40° C.; andNozzle pressure: 100 bar; Injection: 4 mg/ml; collection method: fixedtime).

Two product fraction groups were collected.

The solvent of the first eluted fraction group (the (A)-group, stereocentre marked with

*R; relative stereochemistry) was evaporated, then co-evaporated withMeOH. Yield: 0.019 g of compound 270.

The solvent of the second eluted fraction group (the (B)-group, stereocentre marked with *S; relative stereochemistry) was evaporated, thenco-evaporated with CH₃OH.

Yield: 0.017 g of compound 271.

Example B24

Preparation of Compound 275

Compound 27 (prepared according to B15) (0.133 g; 0.0002 mol) wasdissolved in DMF (2 ml). PS-CDI, 1.9 mmol/g (0.320 g; 0.0006 mol) wasadded and HOBT (0.041 g; 0.003 mol) in DMF (2 ml) was added. Thereaction mixture was shaken for 1 hour at room temperature.1-(2-Methoxyethyl)piperazine (0.0002 mol) in DMF (2 ml) was added. Thereaction mixture was shaken overnight. MP-carbonate, 1 mmol/g (0.5 g)and polymer-bound isocyanate (0.111 g; 0.0002 mol) were added. Thereaction mixture was shaken overnight. The reaction mixture wasfiltered, CH₂Cl₂ (3 ml) was added, and the mixture was shaken for 2hours and filtered again. The filtrate was evaporated with the Genevac.The product was purified by reversed-phase high-performance liquidchromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8μm, 250 g, I.D. 5 cm). A gradient with 3 mobile phases was applied.Phase A: a 0.25% NH₄HCO₃ solution in water; phase B: CH₃OH; phase C:CH₃CN). The desired fractions were collected and the solvent wasevaporated. Yield: 22 mg of compound 275.

Example B25

Preparation of Compounds 299 and 300

3-Chloro-benzenecarboperoxoic acid (3333.18 mg; 1.931 mmol) was added toa solution of compound 223 (prepared according to B6.e) (886 mg; 1.485mmol) in DCM (20 ml) and CH₃OH (20 ml) and stirred at room temperature.The reaction was evaporated to dryness at 30° C. The product waspurified by reversed-phase high-performance liquid chromatography(Shandon Hyperprep® C₁₈ BDS (Base Deactivated Silica) 8 μm, 250 g, I.D.5 cm). A gradient with 3 mobile phases was applied. Phase A: a 0.25%NH₄HCO₃ solution in water; phase B: CH₃OH; phase C: CH₃CN). The twodesired fractions were collected and worked up.

After partial evaporation at 35° C. the two fractions were extractedfirst with EtOAc, followed by DCM, dried (MgSO₄) and worked up yieldingfor fraction A 9 mg from EtOAc extraction and 7 mg residue from DCMextraction. The EtOAc extract of fraction B yielded 15 mg residue and noresidue in the DCM extract. The two remaining aqueous layers wereevaporated to dryness and coevaporated with MeOH/CH₃CN at 30° C.yielding 106 mg from fraction A, 200 mg from fraction B. Fraction A andfraction B were coevaporated with MeOH/CH₃CN at 50° C. Yield: 195 mg ofcompound 299 and 100 mg of compound 300.

Example B26

Preparation of Compound 308

4-Methoxybenzeneacetylchloride (0.162 ml; 0.00106 mol) was added to astirring mixture of intermediate 67 (prepared according to A23.b) (0.37g; 0.00101 mol), NaHCO₃ (0.0934 g; 0.00111 mol) and CH₃CN. The reactionmixture was stirred further under N₂ atm for 18 hours. H₂O (35 ml) wasadded, and stirring was continued for 10 minutes. The product wasfiltered off, washed with 3×H₂O, and dried at 50° C. in vacuo. Yield:0.46 g of compound 308 (89%).

Example B27

Preparation of Intermediate 326

A mixture of intermediate 76 (prepared according to A26.f) (0.0016 mol)in HCl in 2-propanol (2 ml) and 2-propanol (2 ml) was stirred at roomtemperature for 2 hours. The solvent was evaporated. The residue wasstirred in H₂O and NH₄OH (q.s.). This mixture was extracted with CH₂Cl₂.The separated organic layer was dried (MgSO₄), filtered and the solventwas evaporated. The residue was purified by high-performance liquidchromatography (standard gradient elution with NH₄HCO₃ buffer). Theproduct fractions were collected and the solvent was evaporated. Yield:0.160 g of compound 326.

Example B28

Preparation of Intermediate 333

HBTU (722.654 mg; 1.906 mmol) was added to a solution of2,6-dichlorophenyl acetic acid (325.587 mg; 1.588 mmol), intermediate 78(prepared according to A27.b) (539 mg; 1.588 mmol), DIPEA (789.353 mg;4.764 mmol) in DMF dried on molecular sieves (20 ml) and stirred at roomtemperature. The reaction was evaporated to yield 2204 mg. The productwas purified by reversed-phase high-performance liquid chromatography(Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D.5 cm). A gradient with 3 mobile phases was applied. Phase A: a 0.25%NH₄HCO₃ solution in water; phase B: CH₃OH; phase C: CH₃CN). The desiredfractions were collected and partial evaporated at 30° C., extractedwith CH₂Cl₂, dried (MgSO₄) and worked up. Yield: 434 mg of compound 333(52%).

Example B29

Preparation of Intermediate 337

Intermediate 79 (prepared according to A28) (1203 mg; 2.028 mmol) wastreated with a mixture of TFA (2.5 ml; 33.655 mmol) and CH₂Cl₂ (22.5 ml)and stirred at room temperature overnight. The solvent was evaporatedyielding 2.656 g. The residue was extracted with 1 M NaOH/CH₂Cl₂. Afterdrying (MgSO₄) and work up the obtained product was triturated overnightby stirring in diethyl ether. Yield: 944 mg compound 337.

Example B30

Preparation of Intermediate 351

4-Methoxybenzeneacetyl chloride (0.135 g; 0.730 mmol) was added to amixture of intermediate 63 (prepared according to A21.g) (0.272 g; 0.608mmol) and TEA (0.130 ml; 0.912 mmol) dissolved in CH₃CN (5 ml). Thereaction mixture was stirred for 2 hours at room temperature. The formedcrystalline product was filtered off, washed with water, i-PrOH, andhexane and dried on the air. Yield: 0.242 g of compound 351 (67%).

Example B31

Preparation of Intermediate 292

The mixture of compounds mono(phenylmethyl)pentanedioic acid ester(1.478 g; 6.75 mmol), TBTU (2.56 g; 7.84 mmol) and Et₃N (1.71 ml; 12.2mmol) in acetonitrile (50 ml) was stirred for 1 hour at 20° C. Thenintermediate 85 (prepared according to A21.g) was added, and theresulting mixture was stirred for 24 hours more at 20° C. The solutionwas evaporated, the residue was treated with 10%-aqueous solution ofK₂CO₃ (20 ml) and with CH₂Cl₂ (30 ml). The organic layer was separatedand dried over MgSO₄. The solvent was removed in vacuum. The obtainedcrude product (2,843 g) was purified by column chromatography (eluent:EtOAc/Et₃N-1300:1). Yield: 1.262 g of compound 292 (34%).

Table 1 lists the compounds that were prepared according to one of theabove Examples.

TABLE 1

R*, S* = relative stereochemistry

C. Analytical Part

For (LC)MS-characterization of the compounds of the present invention,the following methods were used.

General Procedure A

The HPLC measurement was performed using an Alliance HT 2790 (Waters)system comprising a quaternary pump with degasser, an autosampler, acolumn oven (set at 40° C.), a diode-array detector (DAD) and a columnas specified in the respective methods below. Flow from the column wassplit to a MS detector. The MS detector was configured with anelectrospray ionization source. Mass spectra were acquired by scanningfrom 100 to 1000 in 1 second using a dwell time of 0.1 second. Thecapillary needle voltage was 3 kV and the source temperature wasmaintained at 140° C. Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

General Procedure B

The LC measurement was performed using an Acquity UPLC (Waters) (UltraPerformance Liquid Chromatography) system comprising a binary pump, asample organizer, a column heater (set at 55° C.), a diode-arraydetector (DAD) and a column as specified in the respective methodsbelow. Flow from the column was split to a MS detector. The MS detectorwas configured with an electrospray ionization source. Mass spectra wereacquired by scanning from 100 to 1000 in 0.18 seconds using a dwell timeof 0.02 seconds. The capillary needle voltage was 3.5 kV and the sourcetemperature was maintained at 140° C. (DSC). Nitrogen was used as thenebulizer gas. Data acquisition was performed with a Waters-MicromassMassLynx-Openlynx data system.

General Procedure C

The LCMS analyses for a number of compounds were done at the SurveyorMSQ™ (Thermo Finnigan, USA) comprising a photo diode array detector(PDA; 190-800 nm) and a column as specified in the respective methodsbelow. Flow from the column was split to a MS spectrometer. The MSdetector was configured with APCI (atmospheric pressure chemicalionization, + or − ions). Mass spectra were acquired by scanning from 45to 1000 (of atomic mass unit) in 0.3 seconds. Typical APCI conditionsuse a corona discharge current of 10 μA and a cone voltage of 30 V. TheAPCI probe temperature was 640° C. Nitrogen was used as the nebulizergas. Data acquisition was performed with an Xcalibur™ data system.

Method 1

In addition to general procedure B: Reversed phase UPLC (UltraPerformance Liquid Chromatography) was carried out on a bridgedethylsiloxane/silica (BEH) C18 column (1.7 μm, 2.1×50 mm) with a flowrate of 0.8 ml/min. Two mobile phases (mobile phase A: 0.1% formic acidin H₂O/methanol 95/5; mobile phase B: methanol) were used to run agradient condition from 95% A and 5% B to 5% A and 95% B in 1.3 minutesand hold for 0.2 minutes. An injection volume of 0.5 μl was used. Conevoltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

Method 2

In addition to general procedure A: Reversed phase HPLC was carried outon an Xterra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of 1.6ml/min. Three mobile phases (mobile phase A: 95% 25 mMammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile; mobilephase C: methanol) were employed to run a gradient condition from 100% Ato 1% A, 49% B and 50% C in 6.5 minutes, to 1% A and 99% B in 1 minuteand hold these conditions for 1 minute and reequilibrate with 100% A for1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10V for positive ionization mode and 20 V for negative ionization mode.

Method 3

In addition to general procedure A: Reversed phase HPLC was carried outon a Chromolith (4.6×25 mm) with a flow rate of 3 ml/min. Three mobilephases (mobile phase A: 95% 25 mM ammoniumacetate+5% acetonitrile;mobile phase B: acetonitrile; mobile phase C: methanol) were employed torun a gradient condition from 96% A, 2% B and 2% C, to 49% B and 49% Cin 0.9 minutes, to 100% B 0.3 minutes and hold for 0.2 minutes. Aninjection volume of 2 μl was used. Cone voltage was 10 V for positiveionization mode and 20 V for negative ionization mode.

Method 4 (Only MS)

For a number of compounds only the mass spectra were recorded (no R(t)).The MS detector was configured with an electrospray ionization source.Mass spectra were acquired by scanning from 100 to 1000 in 1 secondusing a dwell time of 0.1 second. The capillary needle voltage was 3 kVand the source temperature was maintained at 140° C. Nitrogen was usedas the nebulizer gas. Data acquisition was performed with aWaters-Micromass MassLynx-Openlynx data system. Cone voltage was 10 Vfor positive ionization mode and 20 V for negative ionization mode.

Method 5

In addition to general procedure C: Reversed phase HPLC was carried outon a Waters XTerra MS C18 column (3.5 μm, 2.1×30 mm) with a flow rate of1.0 ml/min. Two mobile phases (mobile phase A: 0.1% aqueous solution offormic acid; mobile phase B: acetonitrile) were used. First, 100% A washold for 0.1 minutes. Then a gradient was applied to 5% A and 95% B in 3minutes and hold for 0.8 minutes. The injection volume was 1 μl. Thecolumn was at room temperature.

Method 6

In addition to general procedure A: Column heater was set at 60° C.Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 μm,4.6×100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobilephase A: 95% 25 mM ammoniumacetate+5% acetonitrile; mobile phase B:acetonitrile; mobile phase C: methanol) were employed to run a gradientcondition from 100% A to 50% B and 50% C in 6.5 minutes, to 100% B in0.5 minute and hold these conditions for 1 minute and reequilibrate with100% A for 1.5 minutes. An injection volume of 10 μl was used. Conevoltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

Method 7

In addition to the general procedure: Column heater was set at 45° C.Reversed phase HPLC was carried out on an Atlantis C18 column (3.5 μm,4.6×100 mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobilephase A: 70% methanol+30% H₂O; mobile phase B: 0.1% formic acid inH₂O/methanol 95/5) were employed to run a gradient condition from 100% Bto 5% B+95% A in 9 minutes and hold these conditions for 3 minutes. Aninjection volume of 10 μl was used.

Cone voltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

Melting Points

Values are either peak values or melt ranges, and are obtained withexperimental uncertainties that are commonly associated with thisanalytical method.

For a number of compounds, melting points were determined with a DSC823e(Mettler-Toledo). Melting points were measured with a temperaturegradient of 30° C./minute. Maximum temperature was 300° C. (indicated byDSC in Table 2)

For a number of compounds, melting points were obtained with a Koflerhot bench, consisting of a heated plate with linear temperaturegradient, a sliding pointer and a temperature scale in degrees Celsius.(indicated by Kofler in Table 2)

For a number of compounds, melting points were taken on a SanyoGallenkamp melting point apparatus. (indicated by Sanyo Gallenkamp inTable 2)

TABLE 2 Analytical data Comp. Nr. R_(t) [M + H]⁺ Method Melting Points130 1.22 448 1 131 1.26 496 1 129 1.11 444 1 128 0.87 503 1 132 1.20 4881 133 1.20 486 1 127 1.06 491 1 43 1.02 477 1 209.0° C. (DSC) 134 1.21512 1 135 1.31 510 1 126 1.13 492 1 125 0.83 505 1 124 1.33 488 1 123 —472 4 38 1.31 493 1 17 1.35 478 1 140 1.16 449 1 141 1.17 498 1 246.3°C. (DSC) 139 — 445 4 138 0.79 504 1 241.1° C. (DSC) 142 1.13 489 1 1431.14 487 1 137 0.97 492 1 44 0.92 478 1 144 1.15 513 1 58 1.26 511 1114-124° C. (Kofler) 145 1.05 493 1 136 0.74 506 1 1 1.06 489 3 285.3°C. (DSC) 10 1.40 491 1 20 0.86 461 1 122 0.88 463 1 121 0.83 474 1 1200.85 479 1 100 1.23 497 1 119 0.90 501 1 97 1.27 511 1 118 0.98 529 1117 0.96 511 1 116 0.89 475 1 115 1.10 519 1 113 0.88 477 1 112 0.88 4891 111 0.86 491 1 110 0.87 493 1 109 0.82 449 1 98 0.95 519 1 108 0.96517 1 107 1.00 525 1 106 1.16 594 1 105 1.16 594 1 104 1.16 594 1 1031.19 634 1 102 0.95 291 1 101 1.12 652 1 99 1.10 533 1 214 — 535 4 204 —551 4 206 — 535 4 220 — 559 4 209 — 565 4 219 — 549 4 216 — 575 4 39 —575 4 213 — 577 4 33 — 577 4 218 — 549 4 217 — 549 4 208 — 563 4 40 —535 4 205 — 549 4 215 — 577 4 211 — 560 4 210 — 581 4 207 — 561 4 2010.76 476 1 214-216° C. (Sanyo Gallenkamp) 150 3.98 435 2 148 4.29 435 2156 4.10 449 2 159 5.31 475 2 149 4.17 475 2 147 5.33 477 2 157 5.35 4772 23 4.16 449 2 160 4.03 449 2 153 5.00 463 2 158 4.21 435 2 151 4.61449 2 50 1.05 479 1 219.9° C. (DSC) 202 1.01 419 1 245-246° C. (SanyoGallenkamp) 37 0.87 520 1 237.1° C. (DSC) 200 0.73 450 1 245-246° C.(Sanyo Gallenkamp) 21 1.17 498 1 244-246° C. (Sanyo Gallenkamp) 2 1.03518 1 196 0.73 464 1 194-196° C. (Sanyo Gallenkamp) 199 0.78 492 1221-222° C. (Sanyo Gallenkamp) 36 1.18 516 1 254.2° C. (DSC) 22 1.29 5261 248-249° C. (Sanyo Gallenkamp) 182 0.77 479 1 152-154° C. (SanyoGallenkamp) 198 0.82 498 1 260-261° C. (Sanyo Gallenkamp) 197 0.82 512 1251-252° C. (Sanyo Gallenkamp) 180 0.91 504 1 185-187° C. (SanyoGallenkamp) 9 0.84 498 1 187-188° C. (Sanyo Gallenkamp) 26 0.85 569 1232-234° C. (Sanyo Gallenkamp) 181 1.02 540 1 163-165° C. (SanyoGallenkamp) 179 0.79 490 1 220-222° C. (Sanyo Gallenkamp) 195 0.84 512 1172 0.76 583 1 250-252° C. (Sanyo Gallenkamp) 176 0.79 504 1 232-233° C.(Sanyo Gallenkamp) 35 0.92 530 1 169.9° C. (DSC) 178 0.98 546 1 183-184°C. (Sanyo Gallenkamp) 177 0.92 542 1 128-129° C. (Sanyo Gallenkamp) 1940.84 512 1 233-234° C. (Sanyo Gallenkamp) 326 1.27 541 1 203 1.25 711 1193 0.80 498 1 263-264° C. (Sanyo Gallenkamp) 18 1.29 522 1 178.2° C.(DSC) 34 1.30 477 1 142.1° C. (DSC) 175 1.26 729 1 215-216° C. (SanyoGallenkamp) 174 0.92 544 1 192-193° C. (Sanyo Gallenkamp) 32 0.91 556 1188-189° C. (Sanyo Gallenkamp) 173 1.24 741 1 197-199° C. (SanyoGallenkamp) 41 1.11 595 1 186.1° C. (DSC) 4 1.26 532 1 247-249° C.(Sanyo Gallenkamp) 53 1.26 553 1 45 1.05 481 1 178.7° C. (DSC) 189 1.29527 1 238.7° C. (DSC) 29 1.23 555 1 187.3° C. (DSC) 171 1.12 554 1253-255° C. (Sanyo Gallenkamp) 8 1.29 477 1 245.1° C. (DSC) 42 1.31 5251 175.2° C. (DSC) 52 1.35 510 1 48 1.23 527 1 253.4° C. (DSC) 3 1.20 5131 268.2° C. (DSC) 5 1.24 576 1 242.6° C. (DSC) 56 1.04 622 1 218.0° C.(DSC) 54 0.93 639 1 125.4° C. (DSC) 57 1.02 612 1 192 1.20 675 1195-197° C. (Sanyo Gallenkamp) 47 1.31 569 1 51 5.58 570 6 177.8° C.(DSC) 24 1.02 568 1 180.7° C. (DSC) 187 1.29 745 1 6 1.28 745 1 190 1.28541 1 15 1.18 543 1 188 1.25 537 1 208-210° C. (Sanyo Gallenkamp) 1911.14 539 1 96 1.26 457 1 164.7° C. (DSC) 95 1.31 521 1 147.4° C. (DSC)94 1.25 461 1 177.3° C. (DSC) 93 1.30 471 1 189.0° C. (DSC) 59 1.35 5451 234.9° C. (DSC) 92 1.39 501 1 165.4° C. (DSC) 91 1.44 515 1 194.7° C.(DSC) 90 1.33 485 1 214.2° C. (DSC) 60 1.27 491 1 240.7° C. (DSC) 611.35 549 1 241.7° C. (DSC) 89 1.36 499 1 227.2° C. (DSC) 62 1.27 545 1254.0° C. (DSC) 88 1.38 579 1 225.1° C. (DSC) 63 1.34 617 1 218.6° C.(DSC) 87 1.32 533 1 181.2° C. (DSC) 49 1.31 557 1 207.9° C. (DSC) 861.38 499 1 207.8° C. (DSC) 64 1.32 505 1 210.6° C. (DSC) 11 1.33 549 1238.7° C. (DSC) 85 1.42 479 1 202.3° C. (DSC) 84 1.33 527 1 162.2° C.(DSC) 83 1.28 502 1 201.6° C. (DSC) 66 1.31 471 1 181.7° C. (DSC) 821.24 497 1 173.6° C. (DSC) 67 1.21 479 1 187.0° C. (DSC) 68 1.32 485 1223.0° C. (DSC) 81 1.38 545 1 170.3° C. (DSC) 46 1.35 597 1 223.0° C.(DSC) 80 1.32 488 1 79 1.31 489 1 127.1° C. (DSC) 78 1.32 569 1 153.3°C. (DSC) 77 1.34 485 1 200.2° C. (DSC) 76 1.33 487 1 75 1.25 503 1 741.32 518 1 65 1.25 487 1 73 1.26 479 1 141.2° C. (DSC) 72 1.25 515 1 711.27 487 1 183.1° C. (DSC) 70 1.30 511 1 28 1.20 541 1 196.1° C. (DSC)13 1.37 595 1 170 0.99 492 1 169 1.06 506 1 168 1.12 520 1 167 1.18 5341 30 1.21 527 1 175.4° C. (DSC) 12 1.28 519 1 209.8° C. (DSC) 55 1.02554 1 316 1.05 506 1 232-234° C. (Sanyo Gallenkamp) 166 1.05 506 1232-234° C. (Sanyo Gallenkamp) 14 1.02 521 1 217-219° C. (SanyoGallenkamp) 221 2.20 596 5 174-175° C. (Sanyo Gallenkamp) 186 1.40 592 1181-182° C. (Sanyo Gallenkamp) 164 0.92 478 1 236-238° C. (SanyoGallenkamp) 165 1.12 535 1 214-215° C. (Sanyo Gallenkamp) 163 0.96 552 131 1.31 556 1 175-176° C. (Sanyo Gallenkamp) 184 1.28 552 1 162-163° C.(Sanyo Gallenkamp) 185 1.24 542 1 202-203° C. (Sanyo Gallenkamp) 7 1.35586 1 232-233° C. (Sanyo Gallenkamp) 183 1.30 580 1 226-227° C. (SanyoGallenkamp) 16 1.09 529 1 183-184° C. (Sanyo Gallenkamp) 19 1.28 492 1142.3° C. (DSC) 288 1.00 582 1 191.86° C. (DSC) 270 1.26 555 1 271 1.26555 1 315 1.33 526 1 334 1.33 526 1 329 1.33 526 1 335 1.30 569 1179.55° C. (DSC) 289 1.29 546 1 244-245° C. (Sanyo Gallenkamp) 298 1.23540 1 241-242° C. (Sanyo Gallenkamp) 339 1.28 443 1 219.91° C. (DSC) 2741.02 612 1 338 1.31 442 1 146.12° C. (DSC) 293 1.00 568 1 287 1.00 568 1321 1.01 625 1 328 1.01 639 1 306 1.25 612 1 314 1.20 639 1 303 1.09 6451 310 1.02 667 1 291 1.26 626 1 296 1.20 653 1 290 0.99 637 1 294 1.24624 1 275 1.01 681 1 284 1.24 582 1 319 1.33 552 1 160-161° C. (SanyoGallenkamp) 324 1.37 568 1 204-205° C. (Sanyo Gallenkamp) 273 1.30 554 1203-204° C. (Sanyo Gallenkamp) 269 1.02 610 2 301 1.32 554 1 152-153° C.(Sanyo Gallenkamp) 276 1.28 540 1 198-199° C. (Sanyo Gallenkamp) 2811.22 610 1 149-150° C. (Sanyo Gallenkamp) 280 1.16 556 1 227-228° C.(Sanyo Gallenkamp) 348 1.15 504 1 330 1.26 494 1 345 1.26 488 1 295 1.32536 1 349 1.33 536 1 341 1.31 494 1 347 1.24 472 1 350 1.33 501 1 3401.18 474 1 286 1.31 492 1 323 1.31 492 1 309 1.33 510 1 331 1.36 554 1325 1.29 494 1 327 1.29 494 1 344 1.28 476 1 346 1.34 492 1 311 0.96 5561 212-213° C. (Sanyo Gallenkamp) 223 4.94 596 2 252.22° C. (DSC) 2771.21 541 1 297 1.14 507 1 342 1.39 538 1 248 252.90° C. (DSC) 232 4.92596 2 222.04° C. (DSC) 313 1.10 493 1 302 1.19 555 1 279 1.22 521 1 2821.19 507 1 318 0.86 604 1 211-212° C. (Sanyo Gallenkamp) 292 1.00 666 1180-181° C. (Sanyo Gallenkamp) 278 1.07 700 1 172-173° C. (SanyoGallenkamp) 285 1.00 696 1 178-179° C. (Sanyo Gallenkamp) 266 5.46 580 2161.47° C. (DSC) 263 5.43 610 2 132.84° C. (DSC) 308 1.36 514 1 305 0.88639 1 253.39° C. (DSC) 224 5.71 635 6 229.72° C. (DSC) 337 0.90 493 1272 0.91 653 1 234.32° C. (DSC) 283 0.92 639 1 218.59° C. (DSC) 333 1.28526 1 200.57° C. (DSC) 322 0.84 590 1 208.65° C. (DSC) 268 0.97 689 1224.69° C. (DSC) 307 0.93 624 1 206.22° C. (DSC) 300 0.7  628 1 299 0.89612 1 168.24° C. (DSC) 304 0.92 610 1 243.74° C. (DSC) 317 0.87  598* 1248.28° C. (DSC) 226 6.23 694 2 180.97° C. (DSC) 312 6.67 571 7 182.46°C. (DSC) 332 1.32 526 1 236 4.97 643 6 217.37° C. (DSC) 245 1.12 514 1237 242.60° C. (DSC) 240 6.69 626 2 208.87° C. (DSC) 243 6.52 624 2 2460.99 628 1 235-237° C. (Sanyo Gallenkamp) 255 0.95 614 1 176.5-178° C.(Sanyo Gallenkamp) 264 5.39 574 7 223.77° C. (DSC) 228 6.11 653 7220.01° C. (DSC) 259 7.26 430 7 247.07° C. (DSC) 256 8.11 492 7 180.88°C. (DSC) 262 7.64 464 7 175.07° C. (DSC) 260 236.30° C. (DSC) 261226.73° C. (DSC) 257 6.56 483 7 242.27° C. (DSC) 251 6.36 483 7 239.51°C. (DSC) 234 8.61 551 7 251.10° C. (DSC) 239 8.35 517 7 233.85° C. (DSC)238 8.42 517 7 248.47° C. (DSC) 244 266.21° C. (DSC) 241 246.03° C.(DSC) 231 237.34° C. (DSC) 225 8.07 542 7 212.29° C. (DSC) 230 8.19 5427 180.99° C. (DSC) 233 8.34 496 7 244.09° C. (DSC) 229 8.59 532 7242.15° C. (DSC) 258 7.66 472 7 238.35° C. (DSC) 253 246.15° C. (DSC)242 8.20 566 7 172.73° C. (DSC) 254 7.55 527 7 216.89° C. (DSC) 235 6.01526 2 343 5.10 493 6 238.61° C. (DSC) 227 5.55 649 2 250 8.20 514 7 2528.23 518 7 247 1.28 500 1 249 8.02 500 7 352 0.85 577 1 336 1.34 456 1351 0.93 595 1 *for compound 317 [M]⁺ was measured instead of [M + H]⁺R_(t) means retention time (in minutes), [M + H]⁺ means the protonatedmass of the compound, Method refers to the method used for (LC)MS.

TABLE 3 Analytical data Comp. Nr. R_(t) [M − H]⁻ Method Melting Points155 4.12 419 2 146 4.96 459 2 212 — 519 4 27 4.67 553 2 162 1.50 624 1114 0.92 473 1 154 5.06 479 2 161 4.66 463 2 152 4.86 457 2 R_(t) meansRetention time (in minutes), [M − H]⁻ means the deprotonated mass of thecompound (negative mode), Method refers to the method used for (LC)MS.

Optical Rotation

For optical rotation measurement of the compounds of the presentinvention, the following method were used.

The optical rotation was measured using a Perkin Elmer 341 polarimeter.[α]_(D) ²⁰ indicates the optical rotation measured with light at thewavelength of the D-line of sodium (589 nm) at a temperature of 20° C.The cell pathlength is 1 dm. Behind the actual value the concentrationand solvent of the solution which was used to measure the opticalrotation are mentioned. The results are gathered in Table 4.

TABLE 4 Optical rotation Comp. No. [α]_(D) ²⁰ concentration solvent 334−104.4° 0.5 w/v % MeOH 329 +101.2° 0.5 w/v % MeOH 337 −66.6° 0.509 w/v%  MeOH

D. Pharmacological Example

A) Measurement of Inhibition of DGAT1 Activity by the Present Compounds

The inhibiting activity of the present compounds on DGAT1 activity wasscreened in a single well procedure assay using DGAT1 comprisingmembrane preparations and DGAT1 substrate comprising micelles anddetermining formed radio-active triacylglycerol coming in closeproximity of a flashplate surface by radio luminescence.

Said assay is described in full detail in WO2006/067071, the content ofwhich is incorporated herein by reference.

By DGAT1 activity is meant the transfer of coenzyme A activated fattyacids to the 3-position of 1,2-diacylglycerols, thus forming atriglyceride molecule, by enzyme DGAT1.

STEP 1 OF THE ASSAY: Expression of DGAT1

human DGAT1 (NM012079.2) was cloned into the pFastBac vector, containingtranslation start, a FLAG-tag at the N-terminus as described inliterature and a viral Kozak sequence (AAX) preceding the ATG to improveexpression in insect cells. Expression was done as described inliterature (Cases, S., Smith, S. J., Zheng, Y., Myers H. M., Lear, S.R., Sande, E., Novak, S., Collins, C., Welch, C. B., Lusis, A. J.,Erickson, S. K. and Farese, R. V. (1998) Proc. Natl. Acad. Sci. USA 95,13018-13023.) using SF9 cells.

STEP 2 OF THE ASSAY: Preparation of DGAT1 Membranes

72 h transfected SF9 cells were collected by centrifugation (13000rpm-15 min-4° C.) and lysed in 2×500 ml lysisbuffer (0.1M Sucrose, 50 mMKCl, 40 mM KH₂PO₄, 30 mM EDTA pH 7.2. Cells were homogenized by celldisruptor. After centrifugation 1380 rpm-15 min-4° C. (SN discarded),pellet was resuspended in 500 ml lysisbuffer and total cell membranescollected by ultracentrifugation at 34000 rpm(100 000 g) for 60 min (4°C.). The collected membranes were resuspended in lysis buffer, dividedin aliquots and stored with 10% glycerol at −80° C. until use.

STEP 3 OF THE ASSAY: Preparation of DGAT Substrate Comprising Micelles

Materials

a) 1,2-dioleoyl-sn-glycerol, 10 mg/ml (1,2-diacylglycerol (DAG))

-   -   Dissolve in acetonitrile; evaporate the acetonitrile solution        under nitrogen and reconstitute in chloroform at a final        concentration of 10 mg/ml.

b) L-α-phosphatidylcholine, 1 mg/ml (phosphatidylcholine (PC))

-   -   Dissolve in chloroform at a final concentration of 1 mg/ml and        store at 4° C.

c) L-α-phosphatidyl-L-serine, 1 mg/ml (phophatidylserine (PS))

-   -   Dissolve in chloroform at a final concentration of 1 mg/ml and        store at 4° C.

Method

Add 1 ml dioleoyl-sn-glycerol (10 mg/ml) to 10 ml ofL-α-phosphatidylcholine (1 mg/ml) and 10 ml of L-α-phosphatidyl-L-serine(1 mg/ml) in a thick glass recipient. Evaporate under nitrogen and puton ice for 15 minutes. Reconstitute in 10 ml Tris/HCl (10 mM, pH 7.4) bysonication on ice. The sonification process consists of sonificationcycles of 10 seconds in the sonification bath followed by 10 secondscool down on ice and repeating this sonification cycle till ahomogeneous solution is obtained (takes about 15 minutes). The thusobtained micelles are stored at −20° C. till later use and contain DAGat a final concentration of 1.61 mM.

STEP 4 OF THE ASSAY: DGAT FlashPlate™ Assay

Materials

a) Assaybuffer

-   -   50 mM Tris-HCl (pH 7.4), 150 mM MgCl₂, 1 mM EDTA, 0.2% BSA.

b) N-ethylmaleimide, 5M

-   -   Dissolve 5 g into a final volume of 8 ml DMSO 100% and store at        −20° C. in aliquots till later use.

c) Substrate mix (for 1 384 well plate=3840 μl)

-   -   612 μl micelles stock (51 μM final)    -   16.6 μl oleoylCoA 9.7 mM    -   23 μl [³H]-oleoylCoA (49 Ci/mmol, 500 μCi/ml)    -   3188.4 μl Tris pH 7.4, 10 mM

d) Enzyme mix (for 1 384 well plate=3520 μl) (5 μg/ml)

-   -   Add 11.73 μl of DGAT membrane stock (1500 μg/ml stock) to 3508        μl assay buffer.

e) Stop mix (for 1 384 well plate=7.68 ml) (250 mM)

-   -   Add 384 μl of N-ethylmaleimide (5M) to 3.456 ml DMSO 100%, and        further dilute 3.84 ml of said solution with 3.84 ml DMSO 10%.

Method

DGAT activity in membrane preparations was assayed in 50 mM Tris-HCl (pH7.4), 150 mM MgCl₂, 1 mM EDTA and 0.2% BSA, containing 50 μM DAG, 32μg/ml PC/PS and 8.4 μM [³H]-oleoylCoA (at a specific activity of 30nCi/well) in a final volume of 50 μl in 384-well format using the redshifted Basic Image FlashPlate™ (Perkin Elmer Cat.No. SMP400).

In detail, 10 μl enzyme mix and 10 μl substrate mix were added to 30 μlof assay buffer, optionally in the presence of 1 μl DMSO (blank andcontrols) or 1 μl of the compound to be tested. This reaction mixturewas incubated for 120 minutes at 37° C. and the enzymatic reactionstopped by adding 20 μl of the stop mix. The plates were sealed and thevesicles allowed to settle overnight at room temperature. Plates werecentrifuged for 5 minutes at 1500 rpm and measured in Leadseeker.

Experiments with different concentrations of the test compound wereperformed and curves were calculated and drawn based on % CTRL_(min) (%of normalized control). % CTRL_(min) was calculated according toequation 1,

% CTRL_(min)=(sample−LC)/(HC−LC)   Equation 1:

where HC (high control) refers to the median of radioluminescence valuemeasured in the wells with enzyme and substrate but without testcompound, LC (low control) refers to median background radioluminescencevalue measured in the wells with substrate without enzyme and withouttest compound, and sample refers to the radioluminescence value measuredin the wells with substrate, enzyme and test compound at a particularconcentration.

The calculated % CTRL_(min) values form a sigmoidal dose responsedescending curve and from this curve pIC₅₀ values were calculated(−logIC₅₀ where IC₅₀ represents the concentration at which the testcompound gives 50% inhibition of DGAT1 activity). Table 5 shows thepIC₅₀ values for the compounds of formula (I).

In order to determine selectivity of the present compounds for DGAT1compared to DGAT2, the inhibiting activity of the compounds on DGAT2 wasalso determined in the above assay, slightly modified to obtain optimalassay conditions for DGAT2. The tested compounds did not show inhibitingactivity for DGAT2 (Human DGAT2 (NM032564) was cloned and expressed asdescribed in J. Biolog. Chem. 276(42), pp 38870-38876 (2001)).

TABLE 5 pIC₅₀ values (IC₅₀ values expressed in M) Comp. Nr. pIC₅₀ 1 8.352 5.54 3 8.12 4 8.57 5 6.82 6 7.33 7 8.07 8 8.05 9 6.26 10 5.96 11 8.2112 6.74 13 7.53 14 6.50 15 8.34 16 8.33 17 5.65 18 6.92 19 7.51 20 6.2421 7.14 22 7.83 23 5.59 24 7.80 26 6.16 27 7.47 28 8.71 29 8.40 30 8.3531 8.35 32 6.46 33 7.45 34 6.84 35 6.62 36 7.06 37 6.89 38 6.31 39 7.7740 8.11 41 7.11 42 5.16 43 5.30 44 5.29 45 5.63 46 6.48 47 6.87 48 6.8349 6.92 50 7.02 51 7.74 52 7.45 53 7.33 54 7.63 55 7.99 56 7.79 57 7.9758 8.27 59 7.89 60 7.90 61 7.42 62 7.79 63 7.51 64 8.15 65 7.64 66 7.5767 7.22 68 7.91 70 6.86 71 5.97 72 6.31 73 6.34 74 6.76 75 6.22 76 5.2577 5.78 78 6.90 79 5.84 80 6.23 81 5.48 82 7.12 83 5.75 84 5.83 85 5.7186 5.77 87 5.48 88 6.32 89 5.66 90 6.23 91 5.26 92 5.13 93 6.62 94 6.5395 6.90 96 7.12 97 7.31 98 7.30 99 7.59 100 7.06 101 6.86 102 6.28 1036.40 104 6.90 105 6.77 106 6.64 107 6.74 108 6.60 109 5.63 110 5.85 1115.92 112 6.10 113 6.13 114 6.25 115 6.69 116 6.24 117 6.67 118 6.46 1196.41 120 6.08 121 5.42 122 6.25 123 6.06 124 6.78 125 6.19 126 7.17 1275.40 128 5.68 129 6.61 130 7.42 131 7.59 132 7.35 133 7.42 134 7.81 1357.68 136 6.41 137 5.47 138 5.88 139 6.92 140 7.72 141 7.82 142 7.86 1437.74 144 8.24 145 7.26 146 4.98 147 5.06 148 5.15 149 5.14 150 5.16 1515.16 152 5.17 153 5.42 154 5.26 155 5.29 156 5.36 157 5.25 158 5.46 1595.49 160 5.50 161 5.54 162 6.95 163 5.85 164 6.44 165 7.19 166 7.20 1677.65 168 7.51 169 7.27 170 6.61 171 7.55 172 6.22 173 7.46 174 6.46 1757.62 176 5.21 177 6.61 178 7.12 179 5.97 180 6.39 181 7.12 182 5.49 1837.90 184 7.72 185 8.43 186 7.86 187 6.72 188 7.13 189 7.92 190 8.21 1917.35 192 7.68 193 6.47 194 7.47 195 6.91 196 5.17 197 6.91 198 6.64 1995.20 200 5.44 201 5.71 202 6.97 203 7.64 204 5.72 205 6.40 206 6.57 2076.68 208 6.72 209 6.78 210 6.81 211 6.90 212 6.94 213 6.97 214 7.01 2157.23 216 7.46 217 7.58 218 7.64 219 7.71 220 7.72 223 7.70 223.a n.d.224 8.08 225 8.02 226 8.01 227 7.93 228 7.72 229 7.51 230 7.37 231 7.37232 7.33 233 7.30 234 7.30 235 7.27 236 7.22 237 7.20 238 7.20 239 7.13240 7.09 241 6.93 242 6.89 243 6.89 244 6.88 245 6.84 246 6.82 247 6.81248 6.80 249 6.79 250 6.76 251 6.72 252 6.63 253 6.57 254 6.50 255 6.47256 6.38 257 6.18 258 6.12 259 5.87 260 5.81 261 5.65 262 5.49 263 5.43264 5.40 265 5.33 266 5.21 267 6.97 268 8.77 269 8.69 270 8.67 271 8.49272 8.46 273 8.43 274 8.40 275 8.38 276 8.37 277 8.34 278 8.31 279 8.17280 8.17 281 8.14 282 8.11 283 8.10 284 8.09 285 8.04 286 8.02 287 8.00288 8.00 289 7.99 290 7.98 291 7.98 292 7.97 293 7.91 294 7.91 295 7.86296 7.83 297 7.82 298 7.76 299 7.72 300 7.70 301 7.68 302 7.68 303 7.67304 7.66 305 7.61 306 7.58 307 7.53 308 7.50 309 7.45 310 7.43 311 7.36312 7.35 313 7.34 314 7.29 315 7.23 316 7.20 317 7.20 318 7.19 319 7.18320 7.13 321 7.04 322 7.04 323 7.01 324 6.97 325 6.94 326 6.90 327 6.89328 6.88 329 6.86 330 6.70 331 6.62 332 6.51 333 6.45 334 6.33 335 6.32336 6.16 337 5.61 338 5.59 339 5.51 340 5.45 341 5.43 342 5.40 343 5.39344 5.39 345 5.36 346 5.33 347 5.30 348 5.28 349 5.22 350 5.12 351 6.61352 6.47

B) In Vivo Study for Effect of Test Compound on GLP-1 Plasma Levels

Elevation of GLP-1 plasma levels by a DGAT inhibitor was studied asfollows:

Dogs were deprived from food for a period of 22 hours. At time 0,animals were given a liquid meal, containing 18% fat (w/w), by gavagewith a stomach tube. The test compound was given orally together withthe meal. Afterwards, a postprandial plasma profile was determined forGLP-1. Therefore, blood was collected at predetermined time intervals inice-cooled Vacutainers EDTA-plasma tubes and GLP-1 levels were measuredin the samples taken at 0 hour (just before the meal) and at 0.5, 1, 2,4, 6, 8 and 24 hours after dosing. Six dogs (3 males and 3 females) wereincluded per dosage group and the plasma GLP-1 profile was compared withtheir own GLP-1 profile previously determined in the same conditions butwithout administration of the test compound.

GLP-1 determinations in plasma were performed with a Glucagon-likepeptide-1 (active) ELISA kit 96-well plate of LINCO Research.

Compounds 24, 30 and 223 were tested and were found to increase GLP-1levels. (see FIG. 1 for compound 223).

In addition to the plasma GLP-1 profile, also the plasma triglycerideprofile can be determined and compared with their own triglycerideprofile previously determined in the same conditions but withoutadministration of the test compound. After administration of compound223, triglyceride levels decreased.

E. Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates toa compound of formula (I), including any stereochemically isomeric formthereof, a N-oxide thereof, a pharmaceutically acceptable salt thereofor a solvate thereof; in particular to any one of the exemplifiedcompounds.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

2. Suspension

An aqueous suspension is prepared for oral administration so that eachmilliliter contains 1 to 5 mg of active ingredient, 50 mg of sodiumcarboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol andwater ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) ofactive ingredient in 0.9% NaCl solution.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

1. A compound of formula

including any stereochemically isomeric form thereof, wherein Arepresents CH or N; the dotted line represents an optional bond in caseA represents a carbon atom; X represents —C(═O)—; —O—C(═O)—;—C(═O)—C(═O)—; —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;—C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)p-; —C(═S)—; —NR^(x)—C(═S)—;—Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—; —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—; Z¹represents a bivalent radical selected from C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be substituted withhydroxyl or amino; and wherein two hydrogen atoms attached to the samecarbon atom in C₁₋₆alkanediyl may optionally be replaced byC₁₋₆alkanediyl; Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;—NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—C(═O)—;—NR^(x)—C(═O)—O—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—O—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—;—C(═O)—Z²—; —C(═O)—Z²—O—; —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—;—C(═O)—NR^(x)—Z²—C(═O)—O—; —C(═O)—NR^(x)—Z²—O—C(═O)—;—C(═O)—NR^(x)—O—Z²—; —C(═O)—NR^(x)—Z²—NR^(y)—;—C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; Z²represents a bivalent radical selected from C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be substituted withC₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or aryl; and wherein twohydrogen atoms attached to the same carbon atom in the definition of Z²may optionally be replaced by C₁₋₆alkanediyl; R^(x) represents hydrogenor C₁₋₄alkyl; R^(y) represents hydrogen; C₁₋₄alkyl optionallysubstituted with C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or—S(═O)_(p)-aryl; R¹ represents C₁₋₁₂alkyl optionally substituted withcyano, C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹;aryl¹C₁₋₆alkyl; Het¹; or Het¹ C₁₋₆alkyl; provided that when Y represents—NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;—C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may alsorepresent hydrogen; R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl orR³; R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl, naphtalenyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromaticheterocycle containing 1 or 2 N atoms may optionally be substituted withat least one substituent, in particular one, two, three, four or fivesubstituents, each substituent independently selected from hydroxyl;carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; R⁴ represents hydrogen;C₁₋₄alkyl optionally substituted with hydroxyl or C₁₋₄alkyloxy;R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; Het-C₁₋₄alkyl; aryl;R⁷R⁶N—C(═O)—C₁₋₄alkyl; R⁵ represents hydrogen or C₁₋₄alkyl; R⁶represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; R⁷ representshydrogen or C₁₋₄alkyl; or R⁶ and R⁷ may be taken together with thenitrogen to which they are attached to form a saturated monocyclic 5, 6or 7-membered heterocycle which may further contain one or moreheteroatoms each independently selected from O, S, S(═O)_(p) or N; andwhich heterocycle may optionally be substituted with C₁₋₄alkyl; R⁸represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted withhydroxyl; aryl represents phenyl or phenyl substituted with at least onesubstituent, in particular one, two, three, four or five substituents,each substituent independently being selected from hydroxyl; carboxyl;halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino ormono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl; cyano; amino carbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; aryl¹ represents phenyl,naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl orfluorenyl optionally substituted with at least one substituent, inparticular one, two, three, four or five substituents, each substituentindependently being selected from hydroxyl; oxo; carboxyl; halo;C₁₋₆alkyl optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl oraryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl oraryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl;nitro; amino; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; Het represents a monocyclicnon-aromatic or aromatic heterocycle containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) or N; or a bicyclic ortricyclic non-aromatic or aromatic heterocycle containing at least oneheteroatom each independently selected from O, S, S(═O)_(p) or N; saidmonocyclic heterocycle or said bi-or tricyclic heterocycle optionallybeing substituted with at least one substituent, in particular one, two,three, four or five substituents, each substituent independently beingselected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;—S(═O)_(p)—C₁₋₄alkyl; Het¹ represents a monocyclic non-aromatic oraromatic heterocycle containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) or N; or a bicyclic ortricyclic non-aromatic or aromatic heterocycle containing at least oneheteroatom each independently selected from O, S, S(═O)_(p) or N; saidmonocyclic heterocycle or said bi- or tricyclic heterocycle optionallybeing substituted with at least one substituent, in particular one, two,three, four or five substituents, each substituent independently beingselected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—;hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl;nitro; amino; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; p represents 1 or 2; providedthat if X represents —O—C(═O)—, then R² represents R³; and provided that

is excluded; a N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 2. The compound according to claim 1having the following formula

including any stereochemically isomeric form thereof, wherein Arepresents CH or N; the dotted line represents an optional bond in caseA represents a carbon atom; X represents —C(═O)—; —NR^(x)—C(═O)—;—Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)p-;—C(═S)—; —NR^(x)—C(═S)—; —Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—; —C(═S)—Z¹—;—NR^(x)—C(═S)—Z¹—; Z¹ represents a bivalent radical selected fromC₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of saidC₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally besubstituted with hydroxyl; Y represents NR^(x)—C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—; —NR^(x)—C(═O)—Z²—O—;—NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—C(═O)—;—NR^(x)—C(═O)—O—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—O—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—;—C(═O)—Z²—; —C(═O)—Z²—O—; —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—;—C(═O)—NR^(x)—Z²—C(═O)—O—; —C(═O)—NR^(x)—Z²—O—C(═O)—;—C(═O)—NR^(x)—O—Z²—; —C(═O)—NR^(x)—Z²—NR^(y)—;—C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; Z²represents a bivalent radical selected from C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be substituted withC₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or aryl; and wherein twohydrogen atoms attached to the same carbon atom in the definition of Z²may optionally be replaced by C₁₋₆alkanediyl; R^(x) represents hydrogenor C₁₋₄alkyl; R^(y) represents hydrogen; C₁₋₄alkyl optionallysubstituted with C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or—S(═O)_(p)-aryl; R¹ represents C₁₋₁₂alkyl optionally substituted withcyano, C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; aryl¹; aryl¹C₁₋₆alkyl; Het¹;or Het¹C₁₋₆alkyl; provided that when Y represents —NR^(x)—C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;—C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may alsorepresent hydrogen; R² represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl orR³; R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein saidC₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,1,3-benzodioxolyl may optionally be substituted with at least onesubstituent, in particular one, two, three, four or five substituents,each substituent independently selected from hydroxyl; carboxyl; halo;C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; C₁₋₆alkylcarbonyl; nitro;amino; mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; Het;HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; R⁴ represents hydrogen; C₁₋₄alkyloptionally substituted with hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl;C₁₋₄alkyloxy; Het; aryl; R⁷R⁶N—C(═O)—C₁₋₄alkyl; R⁵ represents hydrogenor C₁₋₄alkyl; R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; R⁷represents hydrogen or C₁₋₄alkyl; or R⁶ and R⁷ may be taken togetherwith the nitrogen to which they are attached to form a saturatedmonocyclic 5, 6 or 7-membered heterocycle which may further contain oneor more heteroatoms each independently selected from O, S, S(═O)_(p) orN; and which heterocycle may optionally be substituted with C₁₋₄alkyl;aryl represents phenyl or phenyl substituted with at least onesubstituent, in particular one, two, three, four or five substituents,each substituent independently being selected from hydroxyl; carboxyl;halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino ormono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl; cyano; amino carbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; aryl¹ represents phenyl,naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl orfluorenyl optionally substituted with at least one substituent, inparticular one, two, three, four or five substituents, each substituentindependently being selected from hydroxyl; oxo; carboxyl; halo;C₁₋₆alkyl optionally substituted with aryl-C(═O)—; hydroxyC₁₋₆alkyloptionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; aminocarbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; Hetrepresents a monocyclic non-aromatic or aromatic heterocycle containingat least one heteroatom each independently selected from O, S, S(═O)_(p)or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocyclecontaining at least one heteroatom each independently selected from O,S, S(═O)_(p) or N; said monocyclic heterocycle or said bi-or tricyclicheterocycle optionally being substituted with at least one substituent,in particular one, two, three, four or five substituents, eachsubstituent independently being selected from hydroxyl; oxo; carboxyl;halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino ormono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; Het¹ represents a monocyclicnon-aromatic or aromatic heterocycle containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) or N; or a bicyclic ortricyclic non-aromatic or aromatic heterocycle containing at least oneheteroatom each independently selected from O, S, S(═O)_(p) or N; saidmonocyclic heterocycle or said bi- or tricyclic heterocycle optionallybeing substituted with at least one substituent, in particular one, two,three, four or five substituents, each substituent independently beingselected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substitutedwith aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be substitutedwith aryl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₆alkyl)amino;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; prepresents 1 or 2; a N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 3. The compound according to claim 1 or 2wherein X represents —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—;—Z¹—C(═O)—; —C(═O)—Z¹—; —Z¹—NR^(x)—C(═O)—; —NR^(x)—C(═S)— or —S(═O)p-.4. The compound according to claim 3 wherein X represents —NR^(x)—C(═O)—or —Z¹—NR^(x)—C(═O)—.
 5. The compound according to claim 4 wherein Xrepresents —NR^(x)—C(═O)—.
 6. The compound according to any one ofclaims 1 to 5 wherein A represents N.
 7. The compound according to anyone of claims 1 to 6 wherein R¹ represents aryl¹ or Het¹.
 8. Thecompound according to claim 7 wherein Het¹ represents morpholinyl,pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, furanyl,imidazolyl, thienyl, pyridyl, 1,3-benzodioxolyl, tetrahydropyranyl, eachof said heterocycles optionally being substituted with one or twosubstituents, each substituent independently being selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, —S(═O)_(p)—C₁₋₄alkyl, aryl,arylC₁₋₄alkyl.
 9. The compound according to claim 7 wherein aryl¹represents phenyl, naphthalenyl or phenyl substituted with one or twosubstituents, each substituent independently being selected fromhydroxyl, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl or Het.10. The compound according to any one of claims 1 to 7 wherein R¹represents phenyl substituted with C₁₋₆alkyloxy.
 11. The compoundaccording to any one of claims 1 to 10 wherein R² represents R³.
 12. Thecompound according to claim 11 wherein R³ represents phenyl,naphthalenyl or 2,3-dihydrobenzofuranyl, each of said cycles beingoptionally substituted with one to five substituents, each of saidsubstituents being independently selected from halo, C₁₋₆alkyloptionally substituted with hydroxy, polyhaloC₁₋₆alkyl, C₁₋₆alkylthio,polyhaloC₁₋₆alkyloxy, carboxyl, hydroxyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, nitro, R⁵R⁴N—C(═O)—,R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl, Het-C(═O)—C₁₋₄alkyl, Het-C(═O)—.
 13. Thecompound according to claim 12 wherein R³ represents phenyl substitutedwith three substituents each independently being selected from halo orHetC₁₋₄alkyl.
 14. The compound according to any one of claims 1 to 11wherein the compound of formula (I) is a compound of formula (I′)

wherein R^(3a) and R^(3a) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3a)represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;—S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl;aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het;HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—.
 15. The compoundaccording to any one of claims 1 to 11 wherein the compound of formula(I) is a compound of formula (I″) A tenth embodiment of the presentinvention are those compounds of formula (I) or any subgroup thereof asmentioned hereinbefore as embodiment wherein the compound of formula (I)is a compound of formula (I″)

wherein R^(3a) and R^(3a) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R³ ¹represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;—S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl;aryl; aryloxy; aryl-C(═O)—C₁₋₄alkyl; arylC₁₋₄alkyl; aryl-C(═O)—; Het;HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—.
 16. The compoundaccording to claim 14 or 15 wherein R^(3a) and R^(3b) each independentlyrepresent halo, C₁₋₆alkyl or C₁₋₆alkyloxy.
 17. The compound according toclaim 16 wherein R^(3a) and R^(3b) each independently represent halo.18. The compound according to any one of claim 14, 15, 16 or 17 whereinR^(3c) represents amino; mono-or di(C₁₋₄alkyl)amino; R⁵R⁴N—C(═O)—;R⁵R⁴N—C₁₋₆alkyl; Het-C(═O)—, HetC₁₋₄alkyl or Het-C(═O)—C₁₋₄alkyl. 19.The compound according to claim 18 wherein R^(3c) representsHetC₁₋₄alkyl.
 20. The compound according to any one of claims 1 to 19wherein p represents
 2. 21. The compound according to any one of claims1 to 20 wherein Y represents —NR^(x)—C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—; —NR^(x)—C(═O)—Z²—O—;—NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—;—C(═O)—Z²—; —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—.
 22. The compoundaccording to any one of claims 1 to 21 wherein Z² representsC₁₋₆alkanediyl or C₂₋₆alkenediyl.
 23. The compound according to claim 21wherein Y represents —NR^(x)—C(═O)—Z²— and Z² represents methylene. 24.The compound according to any one of claims 1 to 23 wherein R^(x)represents hydrogen.
 25. The compound according to any one of claims 1to 24 wherein R^(y) represents hydrogen or C₁₋₄alkyl or —S(═O)_(p)-aryl.26. The compound according to claim 1 having the following formula

wherein A represents CH or N; X represents —O—C(═O)—; —C(═O)—C(═O)—;—NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —S(═O)p-;—NR^(x)—C(═S)—; Z¹ represents C₁₋₆alkanediyl; wherein saidC₁₋₆alkanediyl may optionally be substituted with hydroxyl or amino; andwherein two hydrogen atoms attached to the same carbon atom inC₁₋₆alkanediyl may optionally be replaced by C₁₋₆alkanediyl; Yrepresents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;—NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; —C(═O)—NR^(x)—Z²—;—C(═O)—NR^(x)—Z²—O—; Z² represents a bivalent radical selected fromC₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of saidC₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally besubstituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or aryl;and wherein two hydrogen atoms attached to the same carbon atom in thedefinition of Z² may optionally be replaced by C₁₋₆alkanediyl; R^(x)represents hydrogen or C₁₋₄alkyl; R^(y) represents hydrogen; C₁₋₄alkyl;C₂₋₄alkenyl; or —S(═O)_(p)-aryl; R¹ represents C₁₋₁₂alkyl optionallysubstituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy,C₃₋₆cycloalkyl or aryl; C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl;adamantanyl; aryl¹; Het¹; or Het¹ C₁₋₆alkyl; provided that when Yrepresents —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;—C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may alsorepresent hydrogen; R² represents C₁₋₁₂alkyl or R³; R³ representsphenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or a 6-membered aromaticheterocycle containing 1 or 2 N atoms, wherein said phenyl, naphtalenyl,2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle containing 1or 2 N atoms may optionally be substituted with one, two, three, four orfive substituents, each substituent independently selected fromhydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl; nitro; R⁵R⁴N—C(═O)—;R⁵R⁴N—C₁₋₆alkyl; HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; R⁴represents hydrogen; C₁₋₄alkyl optionally substituted with hydroxyl orC₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; Het-C₁₋₄alkyl; R⁷R⁶N—C(═O)—C₁₋₄alkyl; R⁵represents hydrogen or C₁₋₄alkyl; R⁶ represents C₁₋₄alkyl orC₁₋₄alkylcarbonyl; R⁷ represents hydrogen or C₁₋₄alkyl; or R⁶ and R⁷ maybe taken together with the nitrogen to which they are attached to form asaturated monocyclic 5, 6 or 7-membered heterocycle which may furthercontain one or more heteroatoms each independently selected from O or N;R⁸ represents hydrogen, halo, C₁₋₄alkyl substituted with hydroxyl; arylrepresents phenyl or phenyl substituted with one or two substituents,each substituent independently being selected from halo; C₁₋₆alkyl;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; nitro; aryl¹ represents phenyl ornaphthalenyl; wherein phenyl may optionally be substituted with one ortwo substituents, each substituent independently being selected fromhydroxyl; halo; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl or Het;Het represents a monocyclic non-aromatic or aromatic heterocyclecontaining at least N atom; said monocyclic heterocycle optionally beingsubstituted with one substituent being selected from C₁₋₆alkyloptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylcarbonyl or—S(═O)_(p)—C₁₋₄alkyl; Het¹ represents a monocyclic non-aromatic oraromatic heterocycle containing at least one heteroatom eachindependently selected from N, O or S; or a bicyclic non-aromaticheterocycle containing at least O atom; said monocyclic heterocycle orsaid bicyclic heterocycle optionally being substituted with one or twosubstituents, each substituent independently being selected from halo;C₁₋₆alkyl; C₁₋₆alkyloxy-carbonyl; —S(═O)_(p)—C₁₋₄alkyl; aryl; orarylC₁₋₄alkyl; p represents
 2. 27. A compound according to claim 1wherein the compound is selected from

a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 28. A compound according to claim 1 wherein thecompound is

a pharmaceutically acceptable salt thereof or a solvate thereof.
 29. Acompound according to claim 1 wherein the compound is


30. A compound according to any one of claims 1 to 29 for use as amedicine.
 31. A compound as claimed in any one of claims 1 to 29 for usein the treatment of obesity, hypercholesterolemia, hyperlipidemia,dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty liver,nonalcoholic fatty liver disease, liver fibrosis, non-alcoholicsteatohepatitis or diabetes.
 32. A compound as claimed in claim 31 foruse in the treatment of type II diabetes.
 33. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of a compound asclaimed in any one of claims 1 to
 29. 34. Use of a compound for themanufacture of a medicament for the prevention or the treatment of adisease which can benefit from inhibition of DGAT1, wherein the compoundis a compound of formula

including any stereochemically isomeric form thereof, wherein Arepresents CH or N; the dotted line represents an optional bond in caseA represents a carbon atom; X represents —C(═O)—; —O—C(═O)—;—C(═O)—C(═O)—; —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;—C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)p-; —C(═S)—; —NR^(x)—C(═S)—;—Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—; —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—; Z¹represents a bivalent radical selected from C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be substituted withhydroxyl or amino; and wherein two hydrogen atoms attached to the samecarbon atom in C₁₋₆alkanediyl may optionally be replaced byC₁₋₆alkanediyl; Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;—NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—C(═O)—;—NR^(x)—C(═O)—O—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—O—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—;—C(═O)—Z²—; —C(═O)—Z²—O—; —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—;—C(═O)—NR^(x)—Z²—C(═O)—O—; —C(═O)—NR^(x)—Z²—O—C(═O)—;—C(═O)—NR^(x)—O—Z²—; —C(═O)—NR^(x)—Z²—NR^(y)—;—C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; Z²represents a bivalent radical selected from C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be substituted withC₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or aryl; and wherein twohydrogen atoms attached to the same carbon atom in the definition of Z²may optionally be replaced by C₁₋₆alkanediyl; R^(x) represents hydrogenor C₁₋₄alkyl; R^(y) represents hydrogen; C₁₋₄alkyl optionallysubstituted with C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or—S(═O)_(p)-aryl; R¹ represents C₁₋₁₂alkyl optionally substituted withcyano, C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹;aryl¹C₁₋₆alkyl; Het¹; or Het¹ C₁₋₆alkyl; provided that when Y represents—NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;—C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may alsorepresent hydrogen; R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl orR³; R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl, naphtalenyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromaticheterocycle containing 1 or 2 N atoms may optionally be substituted withat least one substituent, in particular one, two, three, four or fivesubstituents, each substituent independently selected from hydroxyl;carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; R⁴ represents hydrogen;C₁₋₄alkyl optionally substituted with hydroxyl or C₁₋₄alkyloxy;R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; Het-C₁₋₄alkyl; aryl;R⁷R⁶N—C(═O)—C₁₋₄alkyl; R⁵ represents hydrogen or C₁₋₄alkyl; R⁶represents hydrogen; C₁ ₄alkyl; C₁₋₄alkylcarbonyl; R⁷ representshydrogen or C₁₋₄alkyl; or R⁶ and R⁷ may be taken together with thenitrogen to which they are attached to form a saturated monocyclic 5, 6or 7-membered heterocycle which may further contain one or moreheteroatoms each independently selected from O, S, S(═O)_(p) or N; andwhich heterocycle may optionally be substituted with C₁₋₄alkyl; R⁸represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted withhydroxyl; aryl represents phenyl or phenyl substituted with at least onesubstituent, in particular one, two, three, four or five substituents,each substituent independently being selected from hydroxyl; carboxyl;halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino ormono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl; cyano; amino carbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; aryl¹ represents phenyl,naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl orfluorenyl optionally substituted with at least one substituent, inparticular one, two, three, four or five substituents, each substituentindependently being selected from hydroxyl; oxo; carboxyl; halo;C₁₋₆alkyl optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl oraryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl oraryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl;nitro; amino; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; Het represents a monocyclicnon-aromatic or aromatic heterocycle containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) or N; or a bicyclic ortricyclic non-aromatic or aromatic heterocycle containing at least oneheteroatom each independently selected from O, S, S(═O)_(p) or N; saidmonocyclic heterocycle or said bi-or tricyclic heterocycle optionallybeing substituted with at least one substituent, in particular one, two,three, four or five substituents, each substituent independently beingselected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;—S(═O)_(p)—C₁₋₄alkyl; Het¹ represents a monocyclic non-aromatic oraromatic heterocycle containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) or N; or a bicyclic ortricyclic non-aromatic or aromatic heterocycle containing at least oneheteroatom each independently selected from O, S, S(═O)_(p) or N; saidmonocyclic heterocycle or said bi- or tricyclic heterocycle optionallybeing substituted with at least one substituent, in particular one, two,three, four or five substituents, each substituent independently beingselected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—;hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl;nitro; amino; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; p represents 1 or 2; providedthat if X represents —O—C(═O)—, then R² represents R³; a N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 35. Use of a compound of formula (I) as claimed in any one ofclaims 1 to 29 for the manufacture of a medicament for the treatment ofobesity, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixeddyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fattyliver disease, liver fibrosis, non-alcoholic steatohepatitis ordiabetes.
 36. Use according to claim 35 for the treatment of type IIdiabetes.
 37. A process of preparing a compound as defined in claim 1characterized by a) reacting an intermediate of formula (II) with anintermediate of formula (III) in the presence of a suitable dehydrating(coupling) agent, in the presence of a suitable solvent and optionallyin the presence of a suitable base; or reacting an intermediate offormula (II) with an intermediate of formula (III) in the presence of asuitable activating agent, a suitable base and a suitable solvent,

with the variables as defined in claim 1 and with Y¹ representing theremainder of the linker Y besides NR^(x)—C(═O)—Z²—; b) reacting anintermediate of formula (II) with an intermediate of formula (IV)wherein W₁ represents a suitable leaving group, in the presence of asuitable base and a suitable solvent,

with the variables as defined in claim 1 and with Y¹ representing theremainder of the linker Y besides NR^(x)—C(═O)—Z²—; c) reacting anintermediate of formula (V) wherein W₂ represents a suitable leavinggroup, with an intermediate of formula (VI) in the presence of asuitable base and a suitable solvent,

with the variables as defined in claim 1; d) reacting an intermediate offormula (V) with an intermediate of formula (VII) in the presence of asuitable base and a suitable solvent,

with the variables as defined in claim 1 and with R¹ representing anoptionally substituted monocyclic saturated heterocycle linked with anitrogen atom to Z², said R¹ being represented by R^(1a), e)deprotecting an intermediate of formula (VIII) wherein P represents asuitable protecting group, in the presence of a suitable acid and asuitable solvent,

with the variables as defined in claim 1 and with R¹ being substitutedwith NH₂, said R¹ being represented by R^(1′)—NH₂; f) reacting anintermediate of formula (IX) with an intermediate of formula (X) in thepresence of a suitable solvent and optionally in the presence of asuitable base,

with the variables as defined in claim 1 and with X₁ representing adirect bond or Z¹; g) reacting an intermediate of formula (XXI) withCl₃COC(═O)—Cl or C(═O)Cl₂ in the presence of a suitable base and asuitable solvent, followed by reaction with an intermediate of formula(X) in the presence of a suitable solvent and optionally in the presenceof a suitable base,

with the variables as defined in claim 1; h) reacting an intermediate offormula (XI) with an intermediate of formula (X) in the presence of asuitable dehydrating (coupling) agent, a suitable solvent and optionallyin the presence of a suitable base; or reacting an intermediate offormula (XI) with an intermediate of formula (X) in the presence of asuitable activating agent, a suitable base and a suitable solvent,

with the variables as defined in claim 1 and with X₁ representing adirect bond or Z¹; i) reacting an intermediate of formula (XII) whereinW₃ represents a suitable leaving group, with an intermediate of formula(X) in the presence of a suitable base and a suitable solvent,

with the variables as defined in claim 1; j) reacting an intermediate offormula (XIII) wherein W₄ represents a suitable leaving group, with anintermediate of formula (X) in the presence of a suitable base and asuitable solvent,

with the variables as defined in claim 1; k) reacting an intermediate offormula (XIV) with an intermediate of formula (X) in the presence of asuitable solvent,

with the variables as defined in claim 1; l) reacting an intermediate offormula (XV) with an intermediate of formula (X) in the presence of asuitable base and a suitable solvent,

with the variables as defined in claim 1 and with X₁ representing adirect bond or Z¹; m) reacting an intermediate of formula (XVI) whereinW₅ represents a suitable leaving group, with NHR⁴R⁵ in the presence of asuitable solvent,

with the variables as defined in claim 1 and with R² representing R³,said R³ being substituted with R⁵R⁴N—C₁₋₆alkyl, said R² beingrepresented by R^(3′)—C₁₋₆alkyl-NR⁴R⁵; n) reacting an intermediate offormula (XXXIV) with an intermediate of formula (XXXV) in the presenceof DECP, a suitable base and a suitable solvent,

with the variables as defined in claim 1 and with Y² representing theremainder of the Y linker; o) reacting an intermediate of formula(XXXVI) with an appropriate acid in the presence of a suitable solvent,

with the variables as defined in claim 1; p) deprotecting anintermediate of formula (XXXVII) wherein P represents a suitable leavinggroup, with a suitable acid in the presence of a suitable solvent,

with the variables as defined in claim 1 and with X containing Z¹, saidZ¹ being substituted with amino, said X being represented by Z¹(NH₂)—X₂,wherein X₂ represents the remainder of the linker X:

or, if desired, converting compounds of formula (I) into each otherfollowing art-known transformations, and further, if desired, convertingthe compounds of formula (I), into a therapeutically active non-toxicacid addition salt by treatment with an acid, or into a therapeuticallyactive non-toxic base addition salt by treatment with a base, orconversely, converting the acid addition salt form into the free base bytreatment with alkali, or converting the base addition salt into thefree acid by treatment with acid; or, if desired, preparingstereochemically isomeric forms, quaternary amines, solvates or N-oxideforms thereof.